NR 01/2011 (15) 10 PLN (INCL. TAX 5% VAT)
contents 8
15
38
8 Lipid-Based Drug Delivery Systems (LBDDS)
40
Disintegrators – used in tablets
Effectiveness testing. Part I
15
Dietary supplements
– food sold by pharmacists
46
The importance of print inspection
18
Realizing THE QUALITY BY DESIGN CONCEPT
48
The new EU GMP Annex 11
25
Your partner in industry field
for Computerised Systems
28
Wipes for Life Science Cleanrooms
51
Formation of aerosols during absorption
– How to select the best wipe for the job
and effects on the design of gas scrubbing
systems for chemical and pharmaceutical industries
32
PAT the plant designer’s viewpoint
36
Contact Center in Pharma industry
38
Slogans used as trademarks
in pharmaceutical industry
1/2011
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40
56
58
70
56
Transport of Medicines
under Controlled Conditions
58
Logistics of Pharmacy
– A Challenge for Processes and Ways of Thinking
62
Electronic management for pharmacy
66
Recipe for logistics
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68
Medicine packaging as industrial design
and subject of copyright
70
Certified safety guarantee
72
Generic drug market in Central Europe
will grow by 6% per annum between
2011 and 2013
1/2011
from the editors The Farmacom publishing house, the editorial office of the “World of the Pharmaceutical Industry” quarterly cordially invite you to take part in 3 THE WORLD OF THE PHARMACEUTICAL INDUSTRY CONGRESS 2010 Representatives of pharmaceutical manufactures and companies are invited to participate with specialists of the industry in this meeting devoted to the latest trends and technologies employed in pharmaceutical production. Experts from pharmaceutical manufacturing, universities, institutions, and organisations related to the pharmaceutical industry will ensure the high level of the Congress. The thematic scope of the Congress programme will include all of the main stages of pharmaceutical production, from supplies of raw materials to the storage of ready products and their forwarding. The next, June edition of “World of the Pharmaceutical Industry” will be a SPECIAL CONGRESS EDITION, additionally distributed during the Congress. WE ARE LOOKING FORWARD TO SEEING YOU AT THE CONGRESS !!! More information will be soon available on our website http://www.farmacom.com.pl
Editor-in-chief „Świat Przemysłu Farmaceutycznego”
Programme Board: Grzegorz Cessak – President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products 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 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 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
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88 | Polish industry
Lipid-Based Drug Delivery Systems (LBDDS) A novel way forward in drug development Frédéric Carrière Research Director at CNRS, Laboratory of Enzymology at Interfaces and Physiology of Lipolysis, Marseille, France
Oral delivery is the preferred route for drug administration thanks to several advantages over other routes (non invasive, less expensive, less potential for side effects such as injection site reactions, etc.) and is the easiest and most convenient method of drug delivery for chronic drug therapies.
Formulating NMEs for oral delivery is currently one of the
res, one has to keep in mind that the lipophilicity of drugs is
greatest challenges faced by scientists in the pharmaceutical
often tightly associated with their target-binding characteristics
industry. Although it is still believed that combinatorial chemistry
and therefore, their efficacy. The large diversity of NMEs remains
can be used for improving the water solubility of pharmacopho-
today under-exploited.
Key points •• LBDDS improves the solubility/dispersion and the oral bioavailability of poorly soluble drugs. •• Novel formulations of existing drugs using LBDDS can change pharmacokinetics, optimise dose-response and improve the efficacy of patient’s treatment. •• New opportunities are created in the lifecycle management of drugs on the market and extending industrial property using LBDDS.
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Content of formulation (% w/w)
Excipients in formulation Oils: triglycerides or mixed mono and diglycerides Water-insoluble surfactants (HLB<12) Water-soluble surfactants (HLB>12) Hydrophilic cosolvents (e.g. PEG, propylene glycol, transcutol) Table 1: The lipid formulation classification system (LFCS)
Type I 100 -
Type II 40-80 20-60 -
Type IIIA 40-80 20-40 0-40
Type IIIB <20 20-50 20-50
Type IV 30-80 0-20 0-50
(1, 2)
Lipid-Based Drug Delivery Systems (LBDDS) Lipid excipients can enhance oral bioavailability of a poorly water soluble drug primarily by improving its solubility and/or dispersion in the aqueous environment of the gastrointestinal (GI) tract. They
Sensitivity to moisture can also affect the chemical stability of drugs and hence their in vivo performance. This can be addressed by formulating the drug in a lipophilic matrix. LBDDS are usually based on various mixtures of oils, surfac-
can also favourably impact intestinal permeability, stabilise the drug
tants, and cosolvents. They have been classified according to their
and reduce in some particular cases its potential degradation by
composition (table 1 (1,2)).
the digestive enzymes present in the GI tract. Overall, LBDDS can improve drug delivery to the patientâ&#x20AC;&#x2122;s systemic circulation. Since gastrointestinal lipolysis mainly occurs in the small intestine, it has been envisioned that LBDDS could be used for the controlled release of active agents embedded in a digestible lipid matrix. Additionally, LBDDS offer several advantages in the formulation of the drug itself. Nonpolar drugs with low aqueous solubility (i.e. <20 yg/ mL) are more easily solubilised in a lipid matrix. Formulating BCS Class II drugs is often challenging due to difficulties in achieving content uniformity and LBDDS are well adapted for the obtention of isotropic mixtures. Substances with low melting points (i.e. <100°C), including those that are liquid at room temperature, are often hard to formulate into dry powders
LBDDS offer several advantages in drug formulation
and this process usually requires large quantities of excipients.
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10 | Polish industry
LCFS type
Characteristics
Advantages
Disavantages
Type I
Non-dispersing requires digestion
GRAS status; simple; excellent capsule compatibility
Formulation has poor solvent capacity unless drug is highly lipophilic
Type II
SEDDS without water-soluble component
Unlikely to lose solvent capacity on dispersion
Turbid o/w dispersion (particle size 0.25-2Îźm)
Type IIIA
SEDDS/SMEDDS with water-soluble components
Clear or almost clear dispersion; drug absorption without digestion
Possible loss of solvent capacity on dispersion; less easily digested
Type IIIB
SMEDDS with water-soluble components and low oil content
Clear dispersion; drug absorption without digestion
Likely loss of solvent capacity on dispersion
Type IV
Oil-free formulation based on surfactants and cosolvents
Good solvent capacity for many drugs; disperses to micellar solution
Loss of solvent capacity on dispersion; may not be digestible
Table 2: Characteristic features, advantages and disadvantages of various types of lipid formulations (2)
Depending on their composition, LBDDS can present various physical
the intestinal barrier where the absorption of nutrients and most drugs
characteristics (non-dispersed oil phase, emulsions of different sizes,
naturally occurs. The fate of a drug in the GI tract depends on various
micellar and lamellar structures), each characteristic presenting various
physical changes that occur during its dispersion in the contents of
kinds of advantages for monitoring drug solubilisation, dispersion and
the GI tract, the dilution of these contents at various stages of the GI
absorption (Table 2). For instance, lipid formulations of Type IIIA including
tract by the endogenous secretions (saliva, gastric juice, pancreatic
an oil phase and surfactants are the basis for the so-called Self- Emul-
juice, bile), and the digestive process that might in some cases affect
sifying Drug Delivery Systems (SEDDS) that spontaneously generates a
the drug chemical stability (Figure 1). Poorly water soluble drugs would
dispersed oil phase in the presence of water. The size of the lipid particles
precipitate to a large extent and would be inactive if specific vehicles
dispersed in the aqueous phase can be engineered using various lipid/
were not used to solubilise/disperse these drugs in the gastric and
surfactant/cosolvent mixtures and LBDDS forming Self-microemulsions
intestinal contents after oral administration. The main advantage of a
(SMEDDS) and self-nanoemulsions (SNEDDS) are available.
lipid formulation is that a lipophilic drug can remain dispersed in solution throughout its transit in the GI tract. The absorption of the drug in the
Improving the solubility/dispersion and the bioavailability of poorly soluble drugs using LBDDS Drug solubility and absorption are key factors in a drugâ&#x20AC;&#x2122;s efficacy. A drug can only be effective once it has dissolved and permeated through
intestine is then achieved by either passive diffusion of the drug from the lipid vehicle to the membranes of enterocytes (interfacial transfer) or release of the drug upon degradation of the lipid matrix by gastrointestinal lipolysis (Figure 1). These processes are certainly not exclusive and the lipid components of LBDDS, their lipolysis products and the
Figure 1: Lipid drug delivery in the GI tract
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Figure 2: Lymphatic absorption by-passes the liver and reduces first pass metabolism
lipophilic drug are probably re-organised in complex structures with bile
e.g. antiretroviral and anticancer drugs. It was shown with Halofantrine
lipids (bile acids, phospholipids and cholesterol) before reaching the
that the lymphatic drug transport is low in absence of lipid (fasting
brush border of the small intestine where absorption occurs.
conditions), but the coÂŹadministration of the drug with microemulsions
Conventional excipients, such as lactose and cellulose, are not well adapted for the formulation of lipophilic drugs. LBDDS were mainly
of long chain lipids increased significantly the cumulative recovery of the drug in the lymph of dogs (8) and rats (9).
developed after it was observed that the oral bioavailability of poorly water soluble drugs could be increased when they were administered with high fat meals (3, 4). Several lipid-based vehicles for these drugs were used in clinical trials over the last 15 years and LBDDS have enabled many new drugs to be evaluated. The use of LBDDS also augments the uptake of highly lipophilic
Changing pharmacokinetics and optimising drug bioavailability using LBDDS Reformulating existing drugs with poor aqueous solubility using LBDDS may improve their pharmacokinetics and bioavailability, thus achieving a better therapeutic effect. With LBDDS formulations, the
drugs (log P>5, lipid solubility > 50 mg/g) into the lymph system, the
rate of drug absorption estimated from plasma levels (area-under-
favourite route for the lipoproteins (chylomicrons) assembled in the
the- curve (AUC)) and maximum plasma concentration values (Cmax)
enterocytes and further excreted into the lymph. This pathway may
was found to be increased, while the kinetics of absorption (time for
reduce first pass metabolism of the drug in the liver, thus increasing
measuring the maximum plasma concentration of the drug, Tmax)
the drugâ&#x20AC;&#x2122;s oral bioavailability (Figure 2 (5-7)). Direct drug access to the
could be accelerated. The bioavailability of several drugs was thus
intestinal lymphatic system may alter systemic distribution patterns.
enhanced when they were formulated in LBDDS e.g. coenzyme Q10,
This could result in enhanced exposure to the drug and improved ef-
a-tocopherol, cyclosporine A, Probucol (Figure 3) (10), Danazol (11),
ficacy, especially if the agent has a direct effect on the immune system,
Paclitaxel.
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12 | Polish industry In addition to an increased oral bioavailability, drugs formulated
of the self-emulsifying preparation over those of the soft gelatin capsule
in LBDDS have predictable release kinetics. For instance, the dose
product were found to be between 2.1 and 4.1, suggesting an increase
linearity of cyclosporine pharmacokinetics from a microemulsion
in bioavailability of between 210 and 410% (Figure 6). Ibuprofen, mainly
formulation (Sandimmune , Neoral ) is improved when compared to
available in the form of tablets for oral administration, was re¬formulated
the pharmocokinetics obtained with the oil-and-alcohol Sandimmune ®
in a liquid form using lipid nanocapsules and positive effects on drug
formulation (Figure 4) (12).
absorption were observed with an 18% increase in the AUC and a 27%
®
®
Moreover, it has been shown that the absorption of the LBDDS
higher mean residence time when compared to tablets.
Neoral formulation of cyclosporine was less affected by food than ®
the reference formulation (Figure 5). Whereas the rate of cyclosporine absorption is slowed by a fat-rich meal using reference formulation
More recently, some drugs like cyclosporin Gengraf or fenofibrate Genus have been developed in hard gelatine capsules(14).
(Tmax = 4.8 ± 1.8 hours vs. 2.5 ± 0.9 hours in fasting conditions), the rate of absorption of the LBDDS Neoral® formulated cyclosporine is faster
Drug reformulation using LBDDS might be used not only for improv-
and is not significantly changed by food intake (Tmax = 1.5 ± 0.4 hours in
ing pharmacokinetics and bioavailability, but also to extend product
fasting conditions vs. 1.8 ± 0.7 hours in fed conditions) (4). In addition,
lines (lipid formulations, tablets, etc...). In addition, the use of LBDDS
the bioavailability of 180-mg cyclosporine LBDDS formulation (Cmax =
might provide new opportunities to extend industrial property
1011 ± 192 ng/mL) is 1.6-fold the bioavailability of 300-mg cyclosporine
on new applications of existing drug substances, for example,
reference formulation (Cmax = 645 ± 248 ng/mL) in fasting conditions.
an oil-in-water emulsion for encapsulating the poorly soluble anti-cancer
As shown in the case of cyclosporine, LBDDS have already been
drug Paclitaxel® (US Patent 6348491, issued on February 19, 2002).
used to re¬formulate several drugs on the market. Danazol®, launched in 1970, was reformulated in 2008 using a LBDDS containing a digestible surfactant (11). Vitamin E (Natopherol®) marketed as an OTC drug in
Clinical benefits of using LBDDS The main advantage of LBDDS is that patients are able to derive
the US by Abbott since 1972 was reformulated in 2000 with LBDDS to
benefit from potent new oral drugs that, in the absence of these
improve its absorption (13). The self- emulsifying preparation achieved a
improved formulations, would not have reached the clinic. The appropri-
faster rate and higher extent of absorption than the Natopherol formu-
ate selection of lipid excipients and formulation strategies at the earliest
lation available as soft Drug reformulation using LBDDS provides new
stages of drug development can lead to considerable savings in both
opportunities gelatin capsules, under fasting condition. The AUC values
the cost and time to reach the market.
®
Improving pharmacokinetics and bioavailability can help to achieve a better therapeutic effect
Formulacja Probucolu
Cmax (µg/ml-1)
Tmax (h)
AUC0-48h (h µg/ml-1)
SNEDDS Oil solution Powder formulation
1,84 ± 0,53 0,98 ± 0,23 0,24 ± 0,05
5,0 (5,0 – 6,0) 7,0 (5,0 – 8,0) 24,0 (5,0 – 48)
26,2 ± 8,8 19,9 ± 4,1 7,5 ± 2,9
Figure 3: Fasted state study of Probucol oral bioavailability in minipigs. Mean plasma concentration versus time profi les (mean, n=6) for probucol following oral administration (10 mg/kg) to minipigs fasted overnight and fed 4 hours after administration. Probucol was administered in gelatine capsules containing either self-nanoemulsifying drug delivery system (SNEDDS), oil solution or powder formulation. Adapted with permission (10)
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Drugs formulated in LBDDS have predictable release kinetics Figure 4: Relationship between dose and cyclosporine AUC in Sandimmune速 and Neoral速 (LBDDS) formulation. Adapted with permission (12)
Some LBDDS facilitate controlled release of the drug, resulting in more patient friendly dosing schedules - which may lead to better tolerability and, as a result of improved compliance, enhanced efficacy. The pharmacokinetics and bioavailability of LBDDS- formulated drugs are less affected by the presence of food than those of drugs formulated with non-lipid excipients. As a result, patients may not have to coordinate their dietary and drug taking schedules. This flexibility could improve compliance. Figure 5: Cyclosporine plasma concentration-time profiles following single oral administration of the 300-mg reference formulation (A) and 180-mg LBDDS formulation (B) under fasting conditions and with a fat-rich meal to 24 healthy male volunteers. Adapted with permission (4)
LBDDS also permits special formulations to be developed for specific patients, such as oral suspension instead of tablets for children e.g. Griseofulvin (GRIFULVIN速) oral suspension.
Conclusion Although their mechanism of action still remains to be explored at the molecular level, LBDDS have already enabled several new drugs to be developed to treat a range of diseases in innovative ways. From an early stage of development formulation scientists can design and implement strategies to characterise or accurately predict the physicochemical and biological properties of compounds. The empirical trial-and-error approach Figure 6: Mean plasma concentration (賊S.E.M., n 8) of vitamin E as a function of time following oral administration of vitamin E (400 IU) in the form of a self-emulsifying preparation and soft gelatin capsule containing pure soybean oil. Adapted with permission (13)
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with erratic in vitro/in vivo correlations should be replaced by a rational
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14 | Polish industry and systematic approach with formulation scientists fulfilling their
4. E.A. Mueller, J.M. Kovarik, J.B. van Bree, J. Grevel, P.W. Lucker,
conventional role in the development of elegant, efficient and stable
K. Kutz. Influence of a fat-rich meal on the pharmacokinetics of
commercial dosage forms’(15). The number of LBDDS- formulated drugs
a new oral formulation of cyclosporine in a crossover comparison
on the market is currently low but it is expected to rise in the future since most NMEs are poorly water soluble molecules. LBDDS will be required
with the market formulation. Pharm Res 11 (1994) 151-5. 5. C.J. Porter, N.L. Trevaskis, W.N. Charman. Lipids and lipid-based
for exploring the pharmacological effects of the tremendous number
formulations: optimizing the oral delivery of lipophilic
of unexploited NMEs. Both patients and pharmaceutical companies
should derive benefits from a broader use of LBDDS.
6. S.M. Khoo, G.A. Edwards, C.J. Porter, W.N. Charman. A conscious
drugs. Nat Rev Drug Discov 6 (2007) 231-48. dog model for assessing the absorption, enterocyte- based
References – Further reading 1. C.W. Pouton. Formulation of poorly water- soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci (2006). 2. C.W. Pouton. Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies.
Advanced Drug Delivery Reviews 60 (2008).
3. D. Fleisher, C. Li, Y. Zhou, L.H. Pao, A. Karim. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications, Clin Pharmacokinet 36 (1999) 233-54.
metabolism, and intestinal lymphatic transport of halofantrine.
J Pharm Sci 90 (2001) 1599-607.
7. G.A. Edwards, C.J. Porter, S.M. Caliph, S.M. Khoo, W.N. Charman. Animal models for the study of intestinal lymphatic drug transport. Adv Drug Deliv Rev 50 (2001) 45-60. 8. S.M. Khoo, D.M. Shackleford, C.J. Porter, G.A. Edwards, W.N. Charman. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm Res 20 (2003) 1460-5. 9. S.M. Caliph, W.N. Charman, C.J. Porter. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral
Drug reformulation using LBDDS provides new opportunities
Patients are able to derive benefit from potent new oral drugs that, in the absence of these improved formulations, would not have reached the clinic
bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and noncannulated rats. J Pharm Sci 89 (2000) 1073-84. 10. F.S. Nielsen, K.B. Petersen, A. Mullertz. Bioavailability of probucol from lipid and surfactant based formulations in minipigs: influence of droplet size and dietary state. Eur J Pharm Biopharm 69 (2008) 553-62. 11. A. Larsen, R. Holm, M.L. Pedersen, A. Mullertz. Lipid-based formulations for danazol containing a digestible surfactant, Labrafil M2125CS: in vivo bioavailability and dynamic in vitro lipolysis. Pharm Res 25 (2008) 2769-77. 12. E.A. Mueller, J.M. Kovarik, J.B. van Bree, W. Tetzloff, J. Grevel, K. Kutz. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm Res 11 (1994) 301-4. 13. T. Julianto, K.H. Yuen, A.M. Noor. Improved bioavailability of vitamin E with a self emulsifying formulation. Int J Pharm 200 (2000) 53-7. 14. R.G.Strickley. Solubilizing vehicles for oral formulation development, Formulation & Process development. Gilead Sciences, Foster City, chapter 9. 15. H.Benameur. Liquid and semi-solid formulations for enhancing oral absorption; Bulletin technique Gattefossé. June 2006.
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Dietary supplements – food sold by pharmacists
Wioletta Bogusz-Kaliś MSc, Eng. JARS Center For Quality Sp. z o.o.
Dietary supplements are usually sold through pharmacies, on account of their pro-health properties, but this does not mean that they are treated the same as medicines. It is estimated that at least half of the products sold in pharmacies are dietary supplements. Other distribution channels for supplements include general stores, hypermarkets and supermarkets, newsagents, small local shops, petrol stations, herbal medicine shops, and mail order, including online stores. In spite of the development of these other channels, however, pharmacies remain the principal mode of distribution for dietary supplements.
The dietary supplements market is developing robustly all over the
No 71, item 1225, as amended). Dietary supplements are food-
world. Data from the literature shows that 20% of people in Poland use
stuffs intended to supplement a normal diet, being a concentrated
supplements. Very often supplements are used by people practising
source of vitamins or minerals or other substances with nutritional
sports, the elderly, and people with fast lifestyles who do not have
or physiological value. They may consist of just one ingredient
time to eat rationally. Some supplements are used in conjunction with
or many. They should be consumed in small measured quantities.
medical treatments for obesity or for the purpose of improving one’s
They are sold in a form facilitating dosing, such as capsules,
looks or the appearance of the skin. Above all they can be used in
tablets, pills, sachets with powder, ampoules with liquid or bottles
situations where for various reasons it is not possible to consume
with a dropper. The definition emphasises that these are products
the recommended amounts of vitamins and minerals in one’s diet.
which do not have the properties of a medicinal product as defined
Dietary supplements should be distinguished from food products intended for general consumption or for particular nutritional purpo-
in the Pharmaceutical Law. The dietary supplements available on the market can be classified
ses, as they are not intended to replace ordinary food, and they are
according to their purpose: aiding slimming, strengthening the
not consumed in order to obtain energy, which is provided by general
immunological system, helping the locomotor system, delaying the
foodstuffs. Supplements should also not be confused with medicines,
ageing process, helping the nervous system, improving concentration,
which can only be sold in pharmacies and are subject to the Pharma-
giving vitality, aiding the circulatory system, improving the digestive
ceutical Law.
system, maintaining correct eyesight, improving the condition of the skin, hair or nails, or improving sports performance.
What are dietary supplements? Definition and composition Dietary supplements are classified as food, and are thus subject to the legal requirements applicable to foodstuffs. A definition of a dietary supplement is contained in the Act of 26 August 2006 on the safety of food and nutrition (Journal of Laws
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The largest class of supplements consists of vitamin and mineral products, these being a concentrated source of vitamins and/or minerals intended to supplement the diet. The supplements may contain other substances beside vitamins and mineral components, including ingredients of plant origin, amino acids, vital unsaturated fatty acids, fibre, lecithin, bee products, and many others.
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16 | Polish industry of plant origin in dietary supplements. The material composition of dietary supplements, in terms of ingredients of plant origin, is very diverse. These ingredients are usually plants or plant extracts without any strong pharmacological action, used in doses several times lower, or even tens of times lower, than those regarded as therapeutic. Ingredients of supplements can improve health and influence the physiological functions of the body. They can also reduce the risk of illness by maintaining the homeostasis, i.e. the equilibrium of conditions in the bodily environment, making possible the maintenance of good health. However, properties involving the ability to prevent or treat illnesses can be ascribed to medicinal products exclusively, as laid down in the Pharmaceutical Law.
Problems with classification Many doubts often arise concerning the classification of dietary supplements; this applies to so-called borderline products. In 20% of cases the Chief Sanitary Inspector has doubts as to whether a supplement should be registered as a medicine. Currently in the EU the requirements for products of this type are not harmonised. A product classified as a dietary supplement in one member state may be classified as a medicinal product in another. The Polish Pharmaceutical Law, amended in 2007, provides a precise definition of a medicinal product and recognises the priority of the medicinal classification. According to Article 3a of the Law, a product which meets the criteria both for a medicinal product and for another type of product, in particular a dietary supplement or cosmetic, as laid down in other regulations, will be subject to the provisions of the Pharmaceutical Law. It should be remembered that a single product cannot have double status, for example it cannot be marketed both as a medicinal product and as a dietary supplement. That might mislead consumers as to the product’s characteristics, including its type and properties. It should be emphasised that dietary supplements, according to the definition, are not medicines and cannot be labelled in a way similar to medicinal products. The law lays down detailed requirements for the labelling of dietary supplements. The Minister of Health’s Regulation of 18 May 2010 amending the regulation on the content and labelling of dietary supplements
Correct labelling of dietary supplements
contains a list of vitamins and mineral components, with their chemi-
To ensure a high level of health protection for consumers and to
cal forms, approved for use in the production of dietary supplements.
enable them to make the right choice, all products introduced onto
The regulation lists 181 chemical compounds in total which can be
the market must be safe and properly labelled. Dietary supplements
used in supplements. Vitamins and mineral components approved for
intended for the final consumer directly are marketed in packaging.
use must be assimilated and safe for the body. However, neither na-
Labelling includes all information in the form of writing and other
tional nor European Union regulations specify maximum or minimum
markings, including trade marks, trade names, graphic elements
quantities of vitamins and mineral components. Excessive consump-
and symbols, concerning the product and placed on its packaging,
tion of vitamins and mineral components may result in side effects,
label, wrapper, leaflet or tag and in the documents accompanying
thus maximum safe levels of their content in dietary supplements
or referring to the product. To distinguish dietary supplements from
must guarantee that using those products in accordance with the
medicinal products they are marketed, displayed and advertised
manufacturer’s recommendations will be safe. There are also no legal
under the name “dietary supplement”, which may not be replaced
regulations specifying the content of other nutrients or ingredients
with a trade name (invented name) for the foodstuff. When a dietary
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Polish industry | 17 supplement is additionally labelled with a trade name (invented
might be misleading to consumers, as regards the products’ content
name), the phrase “dietary supplement” should be placed in its
or name, quantity, shelf-life, source or place of origin, or methods of
immediate vicinity. Furthermore, dietary supplements are labelled
manufacture or production. It must also not be suggested that the
on their packaging with, among other things, the names of nutrient
product has special properties if all similar food products have those
categories or substances characterising the products or an indication
properties; furthermore a foodstuff cannot be described as having
of their characteristics, the amount to be taken per day, a warning not
actions or properties which it does not have. These requirements
to exceed the recommended daily amount, a statement that dietary
are laid down in the Act on the safety of food and nutrition, for all
supplements cannot be used as a substitute for a varied diet, as well
foodstuffs.
as a statement that dietary supplements should be kept out of reach of small children.
All information concerning a product’s characteristics and actions, known as “claims”, describing or referring to a nutrient’s influence
Information on vitamin and mineral content is expressed in terms
on body growth, development and functioning, as well as its
of percentage of recommended daily intake, in accordance with the
psychological or behavioural function and slimming or weight control
annex to the above-mentioned Regulation on dietary supplements.
properties, if given on the labelling, display or advertising
It is not currently required that dietary supplements be labelled with
of a dietary supplement, must be confirmed by scientific data and
their nutritional value. For a nutrient specified in the name of a dietary
must be possible for the average consumer to understand. In the case
supplement or all ingredients listed on the label which determine the
of food products, which include dietary supplements, it is forbidden
product’s activity, the precise quantities contained in the product must
to make medical claims, i.e. information which states, suggests or
be stated.
implies that the product or its ingredients have therapeutic properties
It should be emphasised that dietary supplements cannot be labelled, advertised or displayed in such a way as to imply that they
or can prevent illnesses. The issue of claims is regulated in Regulation (EC) No 1924/2006
have properties involving the ability to prevent or treat illnesses,
of the European Parliament and of the Council of 20 December 2006
or refer to such properties. There must also be no information that
on nutrition and health claims made on foods. This Regulation contains a list of permitted nutritional claims; the European Commission is still working on the matter of health claims. A list of health claims permitted to be placed on foods, including dietary supplements, was originally planned to be adopted by 31 January 2010. Currently it is predicted that by June 2011 a list of permitted health claims for ingredients other than those of plant origin will be issued in the form of a regulation. Later a list of claims concerning ingredients of plant origin will be drawn up, when evaluation of scientific evidence is complete. When the list of permitted claims comes in force, the labelling will be permitted to contain only claims that have received a positive appraisal.
Summary Dietary supplements can exhibit nutritional and other physiological action, and thus improve the health and influence the functioning of the body; they cannot, however, be ascribed such properties of preventing or treating illnesses as are ascribed to medicinal products. According to scientific opinion, healthy persons eating a varied diet containing diverse products, i.e. fruit, vegetables, whole-grain products, pulses, dairy products, and fish and lean meat, do not need to use dietary supplements. Their use can be justified in the case of incorrect eating leading to nutritional deficiencies. This applies in particular to elderly people, people on slimming diets, those eating limited diets (such as vegans), post-menopausal women and those who are pregnant.
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18 | Polish industry
Realizing
THE QUALITY BY DESIGN CONCEPT Krzysztof Woyna-Orlewicz F1 Pharma Sp. z o.o.
Grzegorz Harańczyk StatSoft Polska Sp. z o.o.
The principal task of medicine manufacturers is to supply their customers with products of appropriate quality. The quality of products is measured in terms of their effectiveness and safety, which in the case of generic medicines means pharmaceutical and biological equivalence to the reference drug. According to the Quality by Design concept, this objective is to be achieved through comprehensive understanding of all aspects of the manufacture of medicinal products [1, 4, 6].
ICH guidelines recommend the use of statistical tools for the carrying
In order to improve control over the manufacture of medicines, in August
out of research and development work [4]. In relation to work involving,
2002 the United States Food and Drug Administration (FDA) launched
among other things, the appropriate selection of the product’s composi-
an initiative to set out a new path for the development of principles for
tion and testing and optimization of the technological process, the DOE
good practice in manufacturing, titled Pharmaceutical Current Good
(Design of Experiments) methodology is applicable.
Manufacturing Practices (CGMPs) for the 21st century [3]. The new
Three examples are given below of the use of statistical tools in
interpretation of GMP is oriented towards assuring product quality
research work aimed at developing a technology for the manufacture
based on broadly defined risk analysis, whose aim is to identify those
of generic medicines. The first example relates to the design of the
elements of systems of production which may have a significant effect
quantitative composition of a product with the use of “mixture designs”.
on the quality of the medicine being produced. The definition of risk
The second example involves testing of the criticality of operational
takes account of the probability of occurrence of adverse events and the
parameters of the technological process, carried out using an screening
losses which such an event may cause. A model of the risk manage-
design. The third example demonstrates the optimization of ranges
ment system is shown in Figure 1 [5].
of critical operational parameters based on a Central Composite Design. The first stage of risk evaluation consists of actions involving
Introduction Issues relating to the quality of medicinal products are continually
identifying the factors which pose a potential danger to the quality of the medicine, identifying the mechanism by which they have an adverse
being addressed by the international organizations charged with
effect on the product parameters, and estimating the probability and
verifying technological processes and approving medicines for sale.
consequences of the occurrence of an adverse event. Next, actions are
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19 Initiate Quality Risk Management Process
taken to minimize the frequency of adverse occurrences. This is the risk control stage, during which safe operational ranges are defined for the
Risk Assessment
factors posing a danger to product quality. The result of this stage is the taking of a decision on acceptance of the risk which a defined factor
Risk Identification
may pose. All actions should be properly documented and communicated to the involved parties, and the results in terms of functioning of the
Risk Analysis
system should be subject to periodic review and evaluation [1, 3, 5, 6]. In relation to technological processes, risk management involves the
Risk Evaluation
gy, which is based on a thorough understanding of the manufacturing process [1]. It has been noted that “quality cannot be tested into prorecommended that systematic prospective testing be carried out based on scientifically grounded methodology, taking account of the holistic nature of the subject, and oriented towards risk evaluation. Solutions of this type are called by the term “Quality by Design”, abbreviated to QbD [4]. The development of a technology for the manufacture of a medicine should address the following issues: •• determination of those properties of the medicine which are of key importance to patients;
Risk Communication
ducts; it should be built in or should be by design.” For this purpose it is
Risk Control Risk Reduction
Risk Acceptance
•• definition of features of the form of the medicine which are of key importance for quality – these are called Critical Quality Attributes (CQAs);
Output / Result of the Quality Risk Management Process
•• appropriate selection of the ingredients of the medicinal product; •• development of a technological process; •• identification of critical parameters for the manufacture of the form of the medicine – these are called Critical Process Parameters (CPPs);
Risk Review
•• optimization of operational ranges for critical parameters;
Review Events
•• development of control methods for the production process, which should make it possible to obtain a product of high quality in a repeatable manner.
Figure 1. Diagram of the risk management process [5]
The CQAs of a medicine are the physical, chemical or microbiological properties of the active substance, excipients, intermediate
By making a faulty product it is easier to understand the functional
products and the final form of the medicine. In the case of tablets
dependence between variables. Process factors whose variability
these include, for example, parameters relating to the size of the
over a limited operational range has a direct and significant effect on
dose of the active substance, mechanical resistance, and speed of
critical quality attributes of the form of the medicine are called critical
dissolution of the active substance. Where justified it is permissible to
parameters [9]. Based on data obtained at the design stage, control
analyse parameters which can be substituted for a medicine’s CQAs.
methods are determined for individual stages of the technological
An example is tablets containing easily soluble active substances.
process. The results of analyses of substances and intermediate
Quality control of the product may be based on the results of testing
products, performed in the course of the manufacture of the medicine
of the time of disintegration of the tablets, omitting tests of the rate of
form, provide a basis for steering the process. For this purpose it is
dissolution of the active substance. Achieving and then maintaining
permitted to make changes which do not go outside the range of the
suitable CQA values is an overriding design goal. The effect of the
defined design space. Application of the proposed solutions may limit
process parameters on the product should be calculated precisely
the number of analyses performed on the finished product, and thus
using DOE (Design of Experiments) methods. The parameters to be
reduce the time needed before the medicine is dissolutiond for sale.
tested define the “design space”, whose boundaries are marked by
For example, uniformity of the content of active substance in tablets
the extrema of the independent variables. The design space should
may be confirmed on the basis of results of measurements carried out
take account of the levels of input variables which lead to a process
during tablet formation, namely analysis of tablet mass and content
response not in accordance with requirements, i.e. CQA parameters
of active substance in tablets using the method of near-infrared
with values not compliant with the specified acceptance criteria.
spectroscopy.
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Risk Management tools
Unacceptable
implementation of a system of innovative Process Analytical Technolo-
20 | Polish industry Measurement results should be collected throughout the product life
points (1/2, 1/2, 0), (1/2, 0, 1/2) and (1/2, 1/2, 0) – marked with the symbol
cycle, up to the time it is taken out of production. The databases created
0 in Figure 2. The test point for a second-degree model is (1/3, 1/3, 1/3),
should be subject to periodic reviews, performed in order to check
marked + in Figure 2 [7].
the functionality of the design space, and when necessary to expand, contract or redefine that space.
The acceptance criterion was taken to be that the coefficient of similarity (f2) of dissolution profiles of active substance from the
The STATISTICA program offers tools which can be used to achieve
reference and the generic medicine should be greater than 50 [1], and
the objectives of the innovative QbD system. Described below are
the angle of repose, being a measure of the flowability of the mixture,
practical examples of statistical design of experiments serving to select
should not exceed 40°.
the ingredients for a medicine, to identify the critical parameters of the manufacturing process, and to optimize their operational ranges.
The factor design methodology enables prediction of the effect of an independent variable of untested value on the process response. For this purpose mathematical models are constructed which explain how
Example 1: selection of the composition of a medicine
a factor influences the product [10].
Research work was carried out to develop a generic medicine. Based on a review of the literature and the results of pre-formulation work, the composition of a form of the medicine was determined (Table 1). Preliminary experiments in a technological laboratory indicated that ingredients A, B, C had a significant effect on the rate of dissolution of the API from the tablets and on the flowability of the powder. The mixture’s flowability is of fundamental importance for the production of tablets with suitable quality parameters. Because of the need to maintain a constant tablet mass, given a fixed quantity of the API and of magnesium stearate, it was necessary for the total quantity of the other three ingredients to remain unchanged. Substance
Quantity [mg]
Properties
API A B C Magnesium stearate
39 60
Active Filler, binder Filler, binder, disintegrant Filler, lubricant Lubricant
Total
100
1
Table 1. Composition of tablets
Figure 2. Experimental design for mixtures
The matrix of an experiment for a selected design, together with the results obtained, is shown in Table 2. A design of this type can be
The goal of the experiment was to determine quantitative ratios of
implemented sequentially. Depending on the results obtained from
the excipients A, B and C so as to obtain a mixture with suitable flowa-
current analysis of mixtures or tablets produced in successive proces-
bility, followed by tablets having fundamentally similar rate of dissolution
ses (configurations), the experiment can be stopped when a model with
to the reference medicine. The experiment was performed using the
satisfactory parameters is obtained, or else continued until all configu-
Mixture designs and triangular surfaces module of the STATISTICA
rations in the matrix have been completed. A sequential approach was
program, applying the assumptions of a randomized simplex-centroid
used, which led to a quadratic model. The value of the coefficient of
design with three input values. The design was generated allowing
goodness of fit indicates that the model explains to
the possibility of elimination of one of the components of the mixture.
a degree of almost 100% the variability of the dependent variables
Under these assumptions, the independent variables A, B and C were
under consideration. The regression coefficients are given in Table 3.
assigned boundary values of 0 (not present in the mixture) and 1 The total sum of mixture components is 1 (100%)
(accounts for 100% of the mixture). STATISTICA permits modification of the design and the entry of limits for the values of the levels of the variables (e.g. under the assumption that each ingredient must be present or that an ingredient cannot account for more than a predefined percentage of the mixture). In most cases the relationship between the input variables and the output variable is unknown. It is then usually assumed that the dependence is a linear or quadratic one. Based on the points with coordinates (1, 0, 0), (0, 1, 0) and (0, 0, 1) – marked with the symbol o in Figure 2 – a linear model is constructed and then tested using the
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Input variables – components A 1 0 0 1/2 1/2 0 1/3
B 0 1 0 1/2 0 1/2 1/3
C 0 0 1 0 1/2 1/2 1/3
Process responses f2 71 65 41 76 48 46 55
Angle of repose 51 47 42 48 38 44 39
Table 2. Experimental matrix and process response parameters
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Polish industry | 21 In the analysis of the effect of the quantity of mixture components on the parameter f2, the resulting model is described by the following quadratic regression equation:
f2=71,06•A+65.06•B+41,06•C+30,79•A•B -33,21•A•C -29,21•B•C
Components and their interactions A B C A•B A•C B•C
Regression coefficient f2
Angle of repose
71,06 65,06 41,06 30,79 -33,21 -29,21
51,22 47,22 42,22 -8,39 -38,39 -6,39
Table 3. Regression coefficients estimated from the quadratic model (for f2: R2=0.9996, for angle of repose: R2=0.9541)
Figure 4. STATISTICA graph showing the effect of quantities of ingredients A, B and C on the angle of repose of the mixture
The influence of individual components is illustrated in Figure 3.
Figure 5. STATISTICA graph showing the effect of quantities of the ingredients A, B and C on the angle of repose of the mixture and the rate of release of API from tablets (f2). The dark area corresponds to the optimum quantitative ratios of the ingredients.
Following analysis of the effect of the investigated factors on the rate Figure 3. STATISTICA graph showing the effect of mixture components A, B and C on the value of the similarity factor (f2) of compared profiles for release of API from tablets
Based on the regression equation we can calculate the optimum quantitative ratios for substances A, B and C. In other words, we can select the quantities of each ingredient of the mixture in such a way as to produce tablets with parameters favouring the occurrence of a maximum value for the indicator f2. Additionally we can define acceptance criteria for the design space, i.e. we can find ranges of factor levels which make it possible to produce tablets with a satisfactory value of the coefficient f2. A similar calculation can also be carried out for the results of analysis of other process responses (e.g. powder flowabilitys). The regression equation describing the effect of the composition of the mixture on its flowability (angle of repose) has the following form: Angle of repose [°] = 51.22•A+47.22•B +42.22•C-8.39•A•B-38.39•A•C-6.39•B•C The relationships obtained are shown in Figure 4.
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of dissolution of the API from the tablets and on the angle of repose of the mixture, the optimum quantities of ingredients were determined. In Figure 5 the dark area represents the quantitative ratios of ingredients A, B, C which lead to a mixture with satisfactory flowability (angle of repose less than 44°) and tablets with suitable rate of dissolution (f2 > 55).
Example 2: selection of critical process parameters [11] The goal of this experiment was to identify the operational parameters of the process (factors, independent variables) which have a critical influence on the quality of the medicinal product. Tests were performed on the process of tablet production by the technique of high-shear granulation and fluid-bed drying. Based on reports from the literature [8] and on the team’s preliminary laboratory experiments, a selection was made of independent process variables with potentially critical importance for the quality of the resulting medicine. The variables were assigned values representing the upper and lower bounds of a wide operational range. The tested process factors and the values assigned to them are given in Table 4.
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22 | Polish industry •• tablet mass loss in friability test less than 1.0%; Independent variables
Lower level
Upper level
Quantity of water used to moisten the initial mixture
200 g water / 874.6 g mixture
350 g wody/ 874,6 g mieszaniny
Speed of main mixer during granulation
150 rpm
450 rpm
Speed of side mixer during granulation
500 rpm
3000 rpm
Time of granulation
1 min
5 min
Temperature of drying air
35ºC
60ºC
Moisture content in granulate
1%
2%
Size of mesh used for calibration
1 mm
2.5 mm
•• more than 85% of the active substance released after 15 minutes; •• tablet disintegration time less than 10 minutes. The results of the factor experiment indicate the occurrence of critical faults in the product. Processes no. 4 and 8 produced tablets with insufficient dissolution of active substance and too long disintegration time (Table 5). Based on statistical analysis aimed at identifying process parameters having a fundamental influence on the dissolution of active substance from the tablets, it was found that there was a statistically significant effect from granulation (effect -3.89; p<0.05) and quantity
Table 4. Independent variables selected for testing
of water used to moisten the powder mixture (effect -3.36; p<0.05), as well as a notable effect from the speed of the main mixer used for
The effect of the various factors on the parameters of the tablets
granulation (effect -2.92; p=0.06).
was tested using a randomized fractional Plackett-Burman design of resolution III, enabling testing of the action of seven variables
a) Effect of quantity of binder solution on dissolution
within eight processes. In order to estimate the error resulting from
of active substance from tablets
the effect of uncontrolled variables, three additional processes were carried out, during which the independent variables were assigned intermediate (central) values. The matrix for the experiment is given in Table 5. In the course of 11 technological processes carried out in accorRelease [%]
dance with the assumptions of the experimental matrix, granulates were produced which were then pressed into tablets. The tablets were analysed in terms of mass uniformity, hardness, friability, disintegration time and dissolution. It was assumed that the product ought to meet the following acceptance criteria: •• mass of each tablet in the range average mass ± 5%;
Quantity of solution
Effects (process responses)
Tested factors [k]
Mesh size [mm]
Ave. ± 5%
Min. 85%
Max. 1 %
Disintegration time [min]
Moistness Temp. of granulate [°C] [%]
Auxiliary Hardness [N]
Calibration
Grindability [%]
Drying
Release [%]
Main
Granulation
Mass uniformity min–max [%]
Moistening
1
200
150
500
5
60
2
1,0
- 1,0 + 0,6
96
0
165
5½
2
350
150
500
1
35
2
2,5
- 1,4 + 1,3
100
0
157
8¼
Proces no.
Quantity of Speed of Speed of water main mixer side mixer [g] [rpm] [rpm] 1
2
3
Time of granul-ation [min] 4
5
6
7
3
200
450
500
1
60
1
2,5
- 2,0 + 1,0
112
0
132
9¼
4
350
450
500
5
35
1
1,0
- 0,6 + 0,4
43
0
148
11 ¼
5
200
150
3000
5
35
1
2,5
- 0,9 + 1,2
95
0
145
6¾
6
350
150
3000
1
60
1
1,0
- 0,7 + 0,6
101
0
144
4¾
7
200
450
3000
1
35
2
1,0
- 0,9 + 0,9
98
0
148
5¾
8
350
450
3000
5
60
2
2,5
- 2,4 + 2,0
28
0
139
17 ¼
C1
275
300
1750
3
47,5
1,5
1,75
- 0,7 + 0,6
101
0
115
4¾
C2
275
300
1750
3
47,5
1,5
1,75
- 0,9 + 0,7
98
0
149
6¾
C3
275
300
1750
3
47,5
1,5
1,75
- 0,9 + 0,9
101
0
142
2¼
Table 5. Experimental matrix representing the assumptions of Plackett-Burman statistics (N = 8, k = 7) supplemented with three processes with variables set at central values (C1, C2 and C3), and the results (effects) of the factor experiment. Grey shading indicates the processes which led to critical features of the medicine
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Polish industry | 23 b) Effect of rotary speed of main mixer on dissolution of active substance from tablets
In summary, the following process parameters were found to have a critical effect: 1. quantity of binder solution; 2. speed of the main mixer during granulation;
Release [%]
3. time of granulation. Carrying out the granulation process with the above variables set to high levels may lead to the production of tablets with long disintegration time, offering insufficient dissolution of the active substance.
Example 3: optimization of critical process parameters The aim of this test was to find safe operational ranges for Main mixer speed
c) Effect of time of granulation on dissolution
process parameters with confirmed critical effect on the rate of dissolution of the product’s active substance. These parameters are as follows: quantity of binder solution used to moisten the powder mixture, rotary speed of the main mixer during granulation, and the time of granulation. Process factors were assigned two levels of
Release [%]
values (Table 6).
Factor
Lower (-1)
Upper (1)
Speed of main mixer [rpm]
100
400
Quantity of water in solution of binding substance [g]
200
350
Time of granulation [s]
60
300
Table 6. Independent variables selected for study
Time of granulation
The acceptance criterion was the requirement of similar API dissolution rate curves for the reference and generic medicines, expressed in
Figure 6. STATISTICA graphs showing absolute values of calculated effects of variables of critical importance for product quality
terms of the coefficient f2 > 50. The task was performed using the STATISTICA program, in the
The negative values for the effects indicate that moistening the
module Experimental Design (DOE) – Central composite designs
powders with a large quantity of water, followed by long massing
(response surface). Response Surface Methodology (RSM) is a set of
performed at high impeller speed, may produce tablets offering
statistical techniques used to model and analyse the effect of several
inadequate dissolution of the active substance (Figure 6). The high value
input variables on a variable representing the system’s response. In
for the coefficient of goodness of fit for the model, R2 = 0.92, indicates
order to determine the response surface, a Central Composite Design
that this estimation explains approximately 92% of the variability in the
(CCD) was used. Designs of this type are a development of two-level
considered dependent variable.
designs, with additional central and axial points.
Assessment of the results of measurements of tablet disintegration times showed a statistically significant influence of two variables: time
By changing the axial length (the distance of the axial points from
of granulation (effect 4.7; p<0.05) and mesh size used to sift the dried
the design centre) and the number of points with all variables set to
granulate (effect 5.1; p<0.05). A shorter time of granulation and use of
central values, it is possible to improve such properties of the design
a smaller mesh size to sift the granulate favour the production of faster
as orthogonality and rotatability. In the case of the three input values,
disintegrating tablets. The value of the coefficient of goodness of fit of
the conditions of rotatability and orthogonality of the matrix are satisfied
the model (R2) is 0.94.
when each of the six axial lengths is 1.68 and there are nine points with variables at central values. This design consists of 23 points (Table 7).
There was not found to be any critical effect from the tested process factors on the other tablet quality parameters, such as mass uniformity,
To estimate the effect of the analysed operational variables on the
friability and hardness. The measurement results obtained do not permit
rate of dissolution of the active substance from the product, a quadratic
the identification of process parameters with a notable effect on those
model was used with a satisfactory goodness-of-fit coefficient
parameters.
R2 = 0.73. The regression equation coefficients are given in Table 8.
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24 | Polish industry
-1 -1 -1 -1 1 1 1 1 -1,68 1,68 0 0 0 0 0 0 0 0 0 0 0 0 0
Time [s]
-1 -1 1 1 -1 -1 1 1 0 0 -1,68 1,68 0 0 0 0 0 0 0 0 0 0 0
-1 1 -1 1 -1 1 -1 1 0 0 0 0 -1,68 1,68 0 0 0 0 0 0 0 0 0
Speed of Quantity of main mixer solution [rpm] [g] 160 160 160 160 339 339 339 339 100 400 250 250 250 250 250 250 250 250 250 250 250 250 250
230 230 319 319 230 230 319 319 275 275 200 350 275 275 275 275 275 275 275 275 275 275 275
f2
108 251 108 251 108 251 108 251 180 180 180 180 60 300 180 180 180 180 180 180 180 180 180
72 52 48 36 58 48 45 32 75 54 69 47 38 50 54 57 55 56 57 56 55 56 54
of dissolution of the active substance from the tablets. a) Mixer speed = 175 rpm (rate I)
Quantity of water in solution
b) Mixer speed = 350 rpm (rate II)
Regression coefficient
Constant
88.339
Mixer speed
-0.0494
Quantity of water in solution
-0.1739
Time of granulation
0.3500
Time of granulation • Time of granulation
-0.0011
Table 8. Regression coefficients for the model
Thus the model obtained took the form: f2= 88.339 – 0.0494•Mixer speed – 0.1739•Quantity of water in solution + 0.35•Granulation time – 0.0011•Granulation time•Granulation time It was planned to carry out the high-shear granulation process on a production scale using a device with dimensions approximately 30 times larger than those of a laboratory device and with two-level regulation of the rotary speed of the main mixer. In order to determine safe operational ranges for the process, guided by Freud’s principle of similarity of dimensionless numbers, the rotary speeds of the main mixer were set at one of two levels: either 175 rpm (rate I) or 350 rpm (rate II). The quantities of solution of the binding substance and the time of granulation were then matched accordingly to each of the two main mixer speeds. The results of this matching are shown in Figure 7. On this basis it was recommended to carry out the technological process
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it is permissible to use a greater quantity of binder solution and to perform granulation for a longer time without adversely affecting the rate
Time [s]
Table 7. CCD for three input values, being operational parameters of granulation, and the responses of particular processes (output variables)
Parameter
with the smaller main mixer speed, namely 175 rpm. In these conditions
Time of granulation
Speed of Quantity of main mixer solution [rpm] [g]
Process responses
Real values
Time of granulation
Coded values
Quantity of water in solution
Figure 7. STATISTICA graph showing the matching of granulation parameters relative to the coefficient f2 expressing the similarity of the active substance dissolution profiles between the reference and generic medicines. The quantities of binder solution and time of granulation were matched to the main mixer rotary speeds, which were set at a) 175 rpm, and b) 350 rpm
Bibliography 1. EMEA, Note for guidance on the investigation of bioavailability and bioequivalence, CPMP/EWP/QWP/1401/98, 2001. 2. FDA, Guidance for Industry PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance, 2004. 3. FDA, Pharmaceutical CGMPs For the 21st Century – A Risk-Based Approach, Final Report, 2004. 4. ICH, Q8 Pharmaceutical development, 2008. 5. ICH, Q9 Quality risk management, 2005. 6. ICH, Q10 Pharmaceutical quality system, 2008. 7. Lewis G.A., Mathieu D., Phan-Tan-Luu R., Pharmaceutical experimental design, Informa Health Care, 1998. 8. Parikh D.M., Handbook of Pharmaceutical Granulation Technology, Marcel Deker, 1997. 9. PQRI, Process robustness – a PQRI white paper, Pharm.Eng. 26 (2006) 1–11. 10. Stanisz A., Przystępny kurs statystyki z zastosowaniem STATISTICA PL na przy-kładach z medycyny, StatSoft 2007. 11. Woyna-Orlewicz K., Planowanie eksperymentów w praktyce w farmacji, [w:] R&D – badania innowacyjne z wykorzystaniem analizy danych, StatSoft 2008. 12. StatSoft, Inc. (2010). STATISTICA (data analysis software system), version 9.1. http://www.statsoft.com/.
More information on the use of data analysis in the pharmaceutical industry can be found at www.statsoft.pl/pharma
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Your partner in industry field mgr farm. Agnieszka Kaczmarczyk General Manager, Fagron Polska
mgr farm. Łukasz Kirzyński
The Fagron company is as a realization of its founder’s dream, who wanted a company able to provide the comprehensive solutions for pharmaceutical compounding. Set up by Ger van Jeveren in 1990, Fagron quickly became a leader in this market segment.
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26 | Polish industry
Quality oriented, modern and comprehensive approach to the needs of customers, implementation of GMP and GDP practices meant that the Fagron brand has become synonymous of the best choice in pharmaceutical formulation and is one of the most recognizable players on the market. The steady increase in sales, customer satisfaction and professional service means the company now operates in 17 countries in Europe, and is the undisputed leader in sales in 9 of these territories. Fagron is not only a provider of components, semi-finished and finished products to the compounding, it is also a leader in the distribution of active substances and excipients for pharmaceutical, cosmetic and veterinary use. Offered raw materials are subject to strict inspection and classification by the International Quality Management team, and are independently analyzed. Fagron suppliers are fully qualified and are cyclically audited. All this efforts are made, to offer to the customers the raw materials that meet the highest standards of safety and quality. The products we deliver meet the requirements of the European monographs and have complete documentation, such as CoA, PDS, MSDS, and on request for most of offered substances we are able to provide (E) DMF or CoS / CEP.
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Polish industry | 27
For over 20 years Fagron company has specialized in the
Fagron numbers
distribution of raw materials used in the industry:
•• Number of divisions – 17
•• pharmaceutical (including veterinary): API, intermediates,
•• Number of owned manufacturing sites – 7 •• Number of employers – 864 (December 2010)
excipients, •• food,
•• Number of products in portfolio – 15 000
•• cosmetic. has shown strong growth in recent years, a trend that is expected to Due to our restrictive approach to quality issues, we are trusted by brand leaders to give our customers the product they need and trusted by customers to provide quality products. By providing full support for certification and qualification we allow our customers to focus on what the most important to them: manufacturing. As part of our services we also offer standard presentations of the materials conditioned in the GMP production zones. We are able to provide exact quantities to fit our customers needs. It helps our customers not to worry about overstock, expiring validity dates and the suitability of raw materials.
continue in the coming years. Another spectacular acquisition completed in 2010 was the purchase of a Brazilian leader in the compounding- the company DEG. As Mr Ger van Jeveren, CEO of Fagron says: „The acquisition of DEG is an important milestone in Fagron’s history. Until the beginning of 2010, Fagron was only active in Europe. With the acquisition in mid-May of the already fully integrated American Gallipot and the acquisition of Brazilian DEG, within one year Fagron has become the worldwide market leader. Potential acquisitions in Europe, the United States, Canada and Latin America are currently being looked into to further strengthen this position”.
The Company Fagron has announced the directions of its developments in 2010.
Fagron aims to further strengthen its market leadership positions through robust organic growth and a focused buy-and-build strategy. For 20 years the company Fagron hallmarks are quality and develop-
In June of 2010 the acquisition of Gallipot gave the Fagron possibility to enter the US market from a position of strength and forms an ideal
ment. These two values are treated as a priority within the company so that it is able to meet the increasing demands of customers, despite the
platform for rolling-out the Fagron strategy of revitalizing pharmaceutical
rising market conditions.
compounding and profiting from the increasing demand for tailor-made
Translation: MRPharm Jonathan Fawdry - General Manager, Fagron UK
medication. The market for pharmaceutical compounding in the US
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Wipes for Life Science Cleanrooms – How to select the best wipe for the job Karen Rossington Marketing Manager, Shield Medicare Ltd.
Much has been written about the use of wipes in the electronics industry, but little or nothing about the requirements for wipes within life science cleanrooms. The assumption has also been made that life science requirements are very similar. However, in reality the industries have very different requirements and the specification for one does not necessarily meet the needs of the other. This article will help pharma biotech users decide whether they are using the right kind of wipes for their application.
Differences in specification Electronics cleanrooms place their highest priority on removing particulates from the environment, through the use of sophisticated
where removing the biofilm ensures the disinfectant can reach all surface organisms. In Grade A and B areas it is essential that the wipes and packaging
air filtering and HVAC systems. When it comes to cleaning surfaces or
are sterile. Consideration should also be given to how easy they are
product, they require the wipe to remove any soiling, particulates or
to transfer in to the cleanroom and to ensure that the packaging does
liquid without causing any abrasion to the surface. It is also essential
not generate any particles. In principle, the closer you get to product
that the wipe itself does not contribute any particulates to the envi-
contact areas, the higher the grade of wipe needs to be.
ronment, so the structure, composition and cleanliness of the material is very important. There are no requirements for control of microbial
Why wipe?
contamination within the room, so the wipes do not need to be used in
The key reasons are:
conjunction with disinfectants and are not required to be sterile.
•• Removal of physical soiling and residues
For pharmaceutical and biotechnology companies, the level of
•• More effective disinfection
particulates, although important, is not necessarily as critical. Here,
•• Convenience and ease of use
the primary concern is the application of a disinfectant and subsequent
•• Reduced environmental impact
removal of microbial contamination. Consequently, the wipes need to be effective at removing non viable particulates, capable of applying a
While HEPA filters and air handling systems can automatically
disinfectant, and capable of the subsequent removal of viable contami-
maintain the required non viable particulate levels in the air, any surface
nation. It is also important the wipe does not contribute to the bioburden
contamination must be physically removed. Surfaces need to be
or generate additional particulates.
cleaned before disinfection and the more efficient the cleaning cycle is
In direct contrast to electronics use, a surface resistance to the wipe maybe desirable - this will enable the resulting physical action of wiping to break up the biofilm layer of micro-organisms. This action is known to be very important in the effective control of microbial contamination
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at removing soiling and residues, the more effective the disinfection regime will be. When disinfecting cleanroom surfaces or products for transfer, spraying with disinfectant and wiping is found to be much more effective
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29 than spraying alone - especially against bacterial spores. As already mentioned, this is because the action of wiping helps to break down the biofilm that protects organisms from the disinfectant. This is clearly demonstrated by the results of work carried out to assess the effectiveness of different liquid disinfection techniques1 (Table 1).
A sterile IPA impregnated wipe was significantly better against spore contamination than spraying alone. The best results were obtained using a separate stage of spraying and then wiping. And it made very little difference to this final result if wiping was followed by spraying.
Factors to consider when choosing a life science cleanroom wipe There are certain key factors which need to be considered when chosing a wipe for use in your cleanroom - low levels of particulates are only part of the decision making process. •• Does the wipe need to be sterile ? •• Would pre-impregnated wipes be more suitable ? •• Is the wipe compatible with the disinfectants used ? •• Does it need to be highly absorbant ? •• Is the packaging suitable for transfer into a Grade A or B room ? •• Will the material help remove the biofilm ? •• Are the wipes packaged in a suitable and cost effective quantity ? •• Are the wipes easy to access and use ?
a laundered material (where all particulates, chemicals and pyrogens
•• Are the wipes prepared and packed in a cleanroom ?
have been removed) in a life science cleanroom.
Considering all these factors will allow you to chose the most suitable and most cost effective wipe for the different areas of your cleanroom.
Wipes materials Knitted polyester with sealed edges is a high grade wipe, popular for product contact areas, as it has virtually no particulates and offers good resistance to abrasion and solvents. It is also more expensive.
What grade does the wipe need to be? There are many types of dry and impregnated wipe available - both
A hydroentangled polyester/cellulose blend is an excellent solution for many applications, creating a robust, absorbent, low-particulate
sterile and non-sterile. For each application the user will need to decide
material. Many wipes are available made from a polyester/cellulose mix,
what composition is preferred, determined by the level of particulates
so compare the specification of the different wipes, as particulate levels
required, potential for product contact and cleanroom grade. Consi-
and absorbency can differ with the weight of the material. Also the %
deration also needs to be given to compatibility with the cleaning and
of polyester to cellulose and the method of entanglement can make a
disinfecting agents being used.
difference to the numbers of particles. Suppliers will be able to supply technical data including gsm, absorbancy, wet and dry tensile strength,
Very often users select a very high grade of wipe, when a more appropriate material would still fall within the acceptable limits for
elongation, number of particles, number of fibres and extractable ions. IES-RP-CC004.2 Evaluating Wiping Materials Used in Cleanrooms and
particulates and pose no threat to the quality of the product.
Other Controlled Environments, published by the Institute of Environmental
For example, there may be no need to use wipes manufactured from
Science, provides test methods for comparing cleanroom wipes. This was
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30 | Polish industry developed for the electronics industry but some elements of the test method are relevant for life science cleanroom wipes. Polyeurethane foam (sponge) is particulate free, non abrasive, highly
Is the packaging the wipes are provided in easy-to-open, especially when wearing a double pair of gloves? Some wipes packaging is provided with an “easy tear” method of opening. This avoids the frustration
absorbent and may be useful in specific situations. However it can be
of trying to tear open polyethene packaging or the need to take scissors
quick to release liquid when squeezed, reducing the operator’s ability to
into the cleanroom. Are the wipes packaged in such a way that they are
control disinfection application, or more probably, a liquid spillage that
easy to remove from the pack/pouch/tub without contaminating the wipe
may be hazardous.
at the same time.
Cotton and cellulose (tissue products) offer excellent
Vaporised Hydrogen Peroxide packaging is also available, which
absorbency but are relatively fragile and contain many
significantly reduces the aeration time during the decontamination cycle
particulates. These can rip easily and shed high numbers
in gassing isolators.
of both fibres and particles making them unsuitable for life
If impregnated wipes are chosen, what format is most suitable for
science cleanrooms.
your application? This may be different in each area. In a preparation
Sterile or Non-Sterile ?
area, or low grade cleanroom, a plastic tub with low shedding aperture
Wipes used in Grade A and B areas should be sterile prior to use.
may be the ideal solution for quick and easy access to a large volume
Some organisations buy non-sterile dry wipes and autoclave them.
of sterile wipes. In the isolator or laminar flow cabinet, a resealable
However there are potential drawbacks to this:
pouch of sterile wipes, which protects the wipes during the cleaning
•• The sterility of the wipes can be difficult or time consuming to
process, may be more suitable. Individually packed sachet wipes are
validate. •• Autoclaving may alter the composition of the wipe material, rendering it structurally unsuitable. •• Repacking requires valuable technician time, which could be spent more profitably on key activities. •• There may be hidden costs associated with on-site sterilisation:
also available. Large mop wipes are supplied in small quantities in foil packs, which provide easy access for clipping onto mop frames.
Dry or pre-impregnated wipes? Dry wipes may be preferable for clearing up spillages, or
extra workload, added production downtime and increased quality
wiping down “to dry” surfaces after cleaning. Dry wipes also
validation requirements.
have the advantage of being versatile for use with different agents. Operator preference or process constraints can also
Employing single-use items is best practice, minimising contamination risk. The purchase of gamma irradiated wipes at 25kGy, guarantees sterility and they are supplied with irradiation and sterility certificates.
be important. In addition, larger dry wipes may be needed for particular cleaning applications. Pre-impregnated wipes can offer certain advantages. For example, in confined spaces or when trying to clean inside equipment, access with a bottle and a wipe can be difficult. In isolators or laminar flow cabinets it is not advisable to spray liquid that might seep inside equipment
High quality wipes are available from many suppliers, however they
or pool in a difficult-to-reach area, as this could leave residues or cause
may not be packed ideally for a pharmaceutical cleanroom environment.
damage, so an impregnated wipe offers a method of controlling the
If the wipes are sterile and provided in bulk packs, will wipes need to be
amount of liquid applied to the surface.
thrown away at the end of each session? Would smaller, double bagged
An impregnated wipe can also be easier for an operator to handle,
packs be more useful? The packaging itself should be low shedding and
especially when items need to be picked up or manipulated to ensure
not generate particles on opening.
successful disinfection.
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Polish industry | 31 Many disinfectants, alcohols notably, have low exposure limits, so the use of an impregnated wipe reduces the amount of disinfectant sprayed into the air, significantly reducing health and safety concerns
have been used. In this case wipes folded in half should be used. Surface wiping or mopping should be carried out from top
relating to occupational exposure limits. Pre-impregnated wipes also
to bottom, from back to front and from cleanest to dirtiest,
help to control the consumption of the disinfectant solution.
changing the wipe at appropriate intervals.
Chosing a pre sterilised, pre-impregnated wipe from a manufacturer also eliminates any risk of incompatibility between the wiper material and the chemical disinfectant. This may be a particular issue where lower grade wipes, containing binders, have traditionally been used.
Summary Consider the acceptable degree of particulates for each area of your cleanroom. But don’t forget that other factors
Large size sterile impregnated wipes for use with mop frames are
are important in a pharmaceutical cleanroom, including
also available. These offer a more suitable and environmentally friendly
sterility requirements, and select the wipe material and
alternative to the traditional bucket and mop system. Other advantages
format accordingly.
include : •• They are the quickest and most convenient method of disinfecting
Contact: krossington@shieldmedicare.com
large surface areas. •• They save additional time by eliminating the need to mix concentrate into a solution or use a bucket system and remove the risk of dilution error.
References 1. Validation of liquid transfer disinfection techniques for transfer of components into hospital pharmacy cleanrooms: Hospital Pharmacist Sept 2001: MG Cockcroft,
•• There is no issue about where to obtain suitable water for dilution, a major inconvenience which has the potential of contamination if the water source is outside the cleanroom area.
D Hepworth, JC Rhodes, P Addison, AM Beaney 2. Wiping Surfaces Clean: Advancing Applications in Contamination Control April 2003: Howard Siegerman.
•• The risk of cleaning fluid becoming contaminated is avoided. •• The highly absorbent wipes remain wet throughout use, ensuring a consistent application of fluid to the whole surface area. •• There is no need to dispose of unused disinfectant in the drainage system, making them much more environmentally friendly. When choosing an impregnated wipe care must to be taken to ensure the wipe is not too saturated, but carries enough impregnate to provide an even and effective surface coverage of disinfectant. Sterile impregnated wipes are available with IPA or denatured ethanol in different sizes. In addition, wipes are also available impregnated with a choice of sterile biocides, including sporicides, and neutral detergents.
Correct use of wipes Once the correct wipe for the particular area or application has been chosen, all of its benefits can be eliminated if wiping is not carried out in a validated manner. Wiping or mopping should never be carried out in a circular motion as this causes the wipe/mop in its dirtiest state to be passed over an area which has just been cleaned. This point needs to be reinforced with operators, as a circular wiping pattern is the most comfortable and convenient according to studies2. The correct technique is to wipe/mop towards you in straight horizontal lines, each time overlapping the previous one by 10-25%. A contaminated wipe/mop should not be passed over an area that has just been wiped, unless in the case of a wipe it is folded and refolded to provide a clean surface. Usually quarterly folds are recommended but must be validated with each operator concerned, as a quarterly fold can lead to confusion as to which surfaces of the wipe
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PAT
Bill Treddenick
Life Sciences Director
Marcin Krawiec Senior Process Control Engineer
The introduction of Process Analytical Technology (PAT) can be viewed from various aspects depending upon your role within pharmaceuticals or biologics production. Bill Treddenick (Life Sciences Director) and Marcin Krawiec (Process Control Engineer) from Lorien Engineering, offer the plant designerâ&#x20AC;&#x2122;s view of incorporating PAT into a production facility.
The majority of articles that have been published on the subject of PAT have centred upon the QA/QC aspects â&#x20AC;&#x201C; and the effect of PAT within regulatory compliance frameworks. Lorien Engineering are technical engineers, working within the life sciences field for 20 years, and also within general process technologies in food, brewing and beverages. This article is written from the aspect of manufacturing plant design, and it reflects on how these changed working practices might affect the design of the facility and its services infrastructure. It looks at some of the issues in installing PAT within an existing facility, and also some of the practical steps companies can take to ensure the full benefit to companies and to public health is delivered.
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the plant designerâ&#x20AC;&#x2122;s viewpoint
For the manufacturers of ethical medicines and treatments, regulatory uncertainty tends to inhibit the introduction of change; whether the change involves a new technology or it is simply a prudent adjustment within the validated process, and this limits the scope for innovation and improvement. Manufacturing processes, including the Standard Operating Procedures (SOPs) are often finalised around the Stage 2 clinical trials (or 1st in-man studies), and these processes become fixed and frozen from this point forward. The Registration File (the licence) for a medicinal product, or the Device Dossier for a medical device, lists and defines process parameters and quality attributes. Most post-approval variations to that file require defined change control protocols to be followed, and this can involve a great deal of effort (cost and time), and will usually involve gathering additional supporting data, additional safety and efficacy testing or even new clinical trials. While this policy has produced good quality and safe products, inhibiting efficiency within drug production is not good for public health with regard to affordability. During the product lifecycle, there are opportunities for process innovations to improve the product quality and cost performance, however they have normally been associated with high costs to change the registration file with the regulators, and for global products, many different regulators. Also, regulators have traditionally had an authoritarian approach when it comes to dealing with manufacturers, happy to state what they will not pass, but not so keen on contributing to the solution. In more recent times, regulators such as the US Food and Drug Administration (FDA) have become more proactive, which is crystallised in their PAT Guidance (first published in 2004). This followed
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34 | Polish industry
an initiative in 2002 entitled “Pharmaceutical CGMPs for the 21st
(tolerances). Careful design work and application knowledge of
Century: A Risk-Based Approach.” This altered paradigm recognises
instrumentation is needed to ensure where, when and how the pro-
that medicines are often too expensive, and it signals a shift from a
cess attributes can be monitored, along with practical tolerances. A
culture of ‘end of line testing’ to one of ‘in process analytical testing’
second issue can occur with regard to the cleaning and sterilisation
which would be more familiar to the rest of the process manufacturing
cycles, where in-line/ on-line instrumentation will need to cope with
community. The word ‘analytical’ is explained in the FDA guidance as,
chemical action and elevated temperatures. A third issue comes
“broadly to include chemical, physical, microbiological, mathematical,
with the physical positioning of monitoring instruments (within
and risk analysis conducted in an integrated manner”. The benefits of
reactors, mixing vessels and pipelines) – sometimes there just is not
this approach are fairly obvious: avoidance of adding value to a batch
enough physical space to get everything mounted correctly in order
that may not be released; the batch can be ‘real time released’ as
to obtain accurate and consistent readings. The final problem to
opposed to spending time in quarantine pending release tests; detailed
handle is one of validation – ensuring there is a means to prove the
process data is gathered enabling process optimisation.
function and accuracy of the instrumentation both at start-up and
The key change required within the manufacturing environment is
throughout the life of the plant.
that production staff fully understand the quality needs of the product, rather than developing and following SOPs that solely capture the
The only way we have found to address all of the above issues is to
processing requirements, and leaving quality to the QC function.
both undertake a classical system validation route (emphasis upon the
For example, the FDA is minded that if greater understanding of the
User Requirement Specification and the Design Qualification), and to
critical issues is achieved by everyone involved in the manufacturing
conduct appropriate design risk reviews such as HAZOP (Hazard and
phase (and why they are critical to product efficacy and quality), then
Operability review) or FMEA (Failure Modes and Effects Analysis), along
the manufacturing process will move from being task driven to quality
with the normal GMP risk assessment.
driven, where the word ‘quality’ incorporates drug efficacy attributes. This lies at the heart of PAT. As with any change, moving to PAT needs careful consideration,
So what are the positive effects of introducing PAT? The first benefit is efficiency of manufacture, which will vary
with input from specialists outside of the QA/QC team in order to
depending on the process and the product, and are likely to come from:
produce a ‘right first time’ solution. An issue that can occur is that,
•• Reducing production cycle times
in leading the project, the QA/QC team will consider what product
•• Preventing rejects, scrap, and re-processing
attributes can and will be tested, along with the performance criteria
•• Real time release
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Polish industry | 35 •• Increasing automation to improve operator safety and reduce human errors
between Research, Quality, Manufacturing, Engineering and Business Systems functions.
•• Improving energy and material use and increasing capacity •• Facilitating continuous processing to improve efficiency and manage variability
In summary, the implications that flow from the introduction of PAT into an existing facility are: •• An altered approach to QA/QC, which drives a change in headcount,
Efficiency also comes from ‘real time release’. ‘End of line testing’ drove the need to create space to store finished product in ‘quarantine’ pending QC testing and QP release. PAT and ‘real time release’ sees the product moving directly from the process to the distribution centre. The next impact is on the QC function. Moving QC into the live manufacturing process should drive a change in QC function and in turn
location and facility area. •• Real time product release (and a reduction in space currently assigned to pre-release quarantine storage). •• The introduction of operatives of a process automation/ engineering calibre. •• Changes to the facility with respect to process flow. •• Through headcount reduction, and product testing changes, the
a different location for the QC facility. The current QC output is a PASS
operation and design of cleanrooms may be altered, including HVAC
or FAIL against lab analysis, whereas in-line process measurement and
design (as heat gains from people in cleanrooms and other GMP
any required corrections (within the allowable limits) are captured on
areas will be lower).
the automated batch release record, and the finished product can be released upon batch completion. As more operational data is collected, process optimisation becomes a real possibility. Another consequence of this new reactive manufacturing environment is the need for staff who are more attuned to in-process
The above factors can lead to a review of the facility infrastructure with respect to media systems (heating and cooling water, purified water/WFI, drainage, process gases and electrical power distribution). When fully embracing the world of PAT, we should not forget to
adjustments. Such people will ideally also possess process technology
include the facility design engineers in the dialogue to ensure that a
experience, and can be central to making further process improve-
thorough risk-based design process can be evidenced, and that the
ments. PAT offers a better platform for establishing a shared dialogue
maximum facility benefits can be realised.
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36 | Polish industry
Contact Center
in Pharma industry Aneta Sar-Podsiadło Contact Center Director, Cardinal Pharma Trade Ltd.
Call Center, Contact Center, Call Customer Service Office and many other names they are today commonly used to describe activities related to customer service in a manner other than in direct contact per person. Are these concepts, however, identical? A seemingly interchangeably used the names mean something completely different. The essential difference between Call Center and Contact Center is a range of services that each of them offers. For example, Call Center, as its name suggests serves only phone contact with the customer. Contact Center offers its customers much more besides contact via telephone - mail, online chat with an employee hotline, often sms, and
quite different to the sale by telephone, where we lose any possibility of non-verbal impact on our interlocutor.
even fax! It all depends on the software used in the service center. First
The solution to these problems is outsourcing those processes to
Contact Centers were very crude systems requiring many exercises to
Contact Center – something which is becoming increasingly common in
control their service and to embrace the vastness of possibilities, which in
Poland. Many companies are interested in this subject, but few of them
practice proved to be a small subset to what they can do today. Currently,
choose the pharmaceutical market claiming it as closed to this type
these systems are fairly intuitive, and even a person not previously
of service – which is a serious error. The pharmaceutical market is an
employed in this industry is able to quickly and efficiently handle them,
unlimited ocean of opportunities for contact center services! Let me give
though not necessarily configured.
you just a simple example of savings - imagine a salesman who goes to a
Is the Contact Center a good solution for the pharmaceutical
meeting with a potential recipient of a pharmaceutical company product
market? Well, it certainly is quite a novelty and a great challenge. Ho-
X, visits the place and if he manages to find any person on the spot
wever, note that it can also become a piggy bank, if you would like
responsible for decision-making regarding the cooperation, he may hear
to setup one on your own. Not only the hardware and software are
a negative response. Calling such a company before, we may identify the
expensive, but also the number of workers to be employed under
need to establish cooperation, which in turn saves time of salesman as
appropriate conditions in the competitive market is not easy. That’s
well as the costs associated with car fuel, not to mention the time.
because wages in the Contact Center are very diverse among different
Contact Center can also be used not only as a support for current
voyevodships - the denial of standard trends on labor market. Next on
company operations or the sales process, but also in seasonal marketing
the list is lease of the contact center office space – possibly a huge cost,
campaigns, such as examining the current needs of the pharmaceutical
not mentioning bills for energy consumption by dozens of computers
companies’ customers, or the level of satisfaction with its services, etc.
and displays, and additional devices necessary for the operation of the
And mostly important - Contact Center is not only responsible for outgoing
system devices. Going forward the cost of telephone calls, a monthly
calls, but what could be even more important the consultants that support
line lease subscription necessary to handle this volume of calls, as
incoming connections, depending on customer needs, at certain times
well as internet link, server, software licenses and many other financial
or around the clock. And here comes the dilemma of supporting such a
expenses related to the technical creation of the Contact Center. The
contact center and the need to build a proper case scenario: the system
problem could stem also from organizational issues, such as providing
is just a device to be programmed accordingly. It’s just a thing that will
appropriately silent workplace for consultants, the maximum number of
play something that we write, but it does not create anything new. This is
positions in the room, maintaining the required spacing between agents
another case for the benefits of abandoning and idea of starting your own
and the required communications routes, as well as the same size
Contact Center and trying to meet the current needs of the company in
desks, etc. Finally, the employment of the relevant managers, relevant
this regard by someone who knows the contact center as the pharmacist
people to optimize the sales process, because direct selling is a really
knows the pharmacy. Mentioned systems need to provide inbound calling
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37
customer the hotline, they need to determine subject of conversation,
information, allowing the consultant a quick assessment of services and
inform about the details of your offer, enable ordering your goods by
products the customer is using.
telephone, and what’s more to enable connection to a consultant who will advise and help explain and dispel any doubts.
Contact Center systems give us a very extensive opportunity to analyze how to use the optimum and most effective time to log into the system a
What we need first is Interactive Voice Response System. At a glance,
certain amount of consultants based on many factors and data. Thanks to this,
IVR allows you to make simple actions via the phone numeric keypad and
there is no way the consultant would be bored by lack of phone calls or that he
listen to the information in the form of recordings. The IVR alone can offer
would be swamped in requests. Today’s systems also enable contact center
us a way to listen to messages, but it can also allow the connection to the
quality control study using the Mystery Caller method, as well as customer
consultant, ordering of call-back service or to express an opinion about
surveys. The first option allows you to contact a hotline or have the system
the company which you are calling, ordering of e-mail/text messages with
call you with any frequency on the phone number assigned to the worker
the information or answers to specific questions - it all depends on how far
controlling the quality of services provided by the Contact Center, so that the
we want to develop an automated tree. It may also allow the person calling
auditor may determine the quality of services offered during the interview. The
to auto-identify herself and order operations such as the redemption of
second option may take place in the form of an outbound campaign where the
points in the loyalty program operated by a pharmaceutical company.
consultant will conduct a short survey on the last contact with the Customer
Contact by phone is a big pool of opportunities, but not the only
Contact Center, or in a more automated way - the same system calls back to
one. There are also electronic solutions such as online chat, or e-ma-
the customer allowing an assessment of the last call of the Contact Center by
il. Using both we have the opportunity to talk with a consultant of the same
selecting the appropriate option from the phone keypad.
contact center but using computer keyboard - which today is chosen by
Contact Center is still immeasurable vastness of possibilities. Every
most people because of the power of the Internet that is growing every
day in the minds of people dealing with this issue are born new ideas and
day. Correspondence mail requires no additional comment. As a rule,
solutions. Today you should look into this issue and consider whether or not
Contact Center uses a signature of operating consultant in the footer. In
it is worth to dive in them right now while the prices of such services are still
the case of online chat conversation, the situation is similar to a phone
affordable. Currently, it is not just a way to stand out, but primarily a way to
call. The chat window is invoked from a web page. It is often possible
significantly reduce costs stemming from established routines to which we got
that logged in customers also automatically provide parts of their profile
accustomed to in the course of time. ADVERTISEMENT
38 | Polish industry 38
Slogans
used as trademarks in pharmaceutical industry Izabella Dudek-Urbanowicz Patent Attorney Patpol
In pharmaceutical industry, as in other branches of market economy, publicity is a key to success. It is important to reach possibly the largest group of customers, attract their attention and enable them to become familiar with the product, which in this case is a medicine.
Customers would certainly not be aware of existence of many pharma-
In consequence, there is a large group of medicines on the market
ceutical products without advertising, which nowadays is omnipresent in
whose names are nearly descriptive, e.g. GRIPEX or GRIPOLEK, and the
our lives. Advertising paves the way for introduction of a new pharmaceu-
owners of those names and trademarks having so similar word elements
tical product on the market, and later helps it function in turnover. Through
and being so close in semantic and visual respect, must resort to other
advertising a pharmaceutical product wins permanent position on the
means in order to attract customers’ attention.
market and customers become well acquainted with it. Pharmaceutical concerns hire advertising companies not only in order
Effective advertising involves not only a catchy name of a medicine, but also an advertising slogan that goes together with it and is later easily
to develop the graphic features of the packaging in which a product will
linked by customers with the product. Inventing such slogan, under which
be offered to customers, but also to create a catchphrase under which the
the whole advertising campaign will be conducted, is a difficult task.
product will appear on the market. An effective advertising campaign must
However, a good idea for a slogan is a key to success on the market, as in
involve more than just a short TV spot, product name or the outer look of
the course of trade customers will easily associate a pharmaceutical pro-
the packaging. The best advertising effects are achieved by the TV spots,
duct with the slogan under which it has appeared. It is easy to remember
in which short but easily remembered slogans appear that stay long in
one of the Polish TV spots featuring a lady called Ms. Gozdzikowa who
customer’s memory.
offers her neighbors the right medicine for a headache, and to keep in
Slogans are a useful tool for pharmaceutical companies, especially
mind the name of that medicine until the need arises.
that the names of medicines used for the treatment of one particular
Slogan is usually a few-word meaningful expression, which is easily
disease may be - and usually are - similar. Medicines are registered
remembered, as it frequently contains a rhyme, and is the motto for the
under commercial names with the Office for Registration of Medicinal
whole advertising campaign. The following slogans have been registered
Products, Medical Devices and Biocidal Products. In addition, the names
as trademarks in Poland:
of medicines are registered as trademarks with the Polish Patent Office.
•• “RENNIE – JUŻ W PORZĄDKU MÓJ ŻOŁĄDKU”
The grant of the right of protection for the name of a medicinal product as a trademark gives its holder a monopoly on its use on the market. However, protecting the name as a word trademark only may not be sufficient for promotion or to exist in customers’ minds. When it comes to the registration of pharmaceutical product names as trademarks, the Polish Patent Office applies more liberal criteria comparing to those applied in relation to the names destined for the marking of other kinds of goods. Pharmaceutical names usually contain words or parts of words which relate directly to the main active substance in the preparation, or a disease for the treatment of which the preparation is used. Using the same prefixes or other elements relating to pharmaceutical industry and medicine is a common practice among the owners of trademarks which are also commercial names of medical preparations.
1/2011
(RENNIE makes your stomach feel good) •• “MANTI. ZGAGA SZYBKOŚCI WYMAGA” (MANTI. Heartburn needs quick remedy) •• “XENNA DZIAŁA JAK NATURA CHCIAŁA” (XENNA works like Mother Nature) •• “RUTINOSCORBIN, BIERZ JAK CIĘ BIERZE” (RUTINOSCORBIN, take it before a cold takes you) •• “VIGOR, BY CIESZYĆ SIĘ ZDROWIEM I CIESZYĆ SIĘ ŻYCIEM” (VIGOR, to enjoy health and to enjoy life) •• “KASZEL MINIE PO FLEGAMINIE” (FLEGAMINA and your cough is over) •• “STAWY DO NAPRAWY?” (Your joints need repairing?)
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39
www.patpol.com.pl •• “COLDREX – KICHAJ NA PRZEZIĘBIENIE” (COLDREX – you sneeze no more) •• “ALTACET ICE. I SZYBCIEJ WRACASZ DO GRY” (ALTACET ICE. And you are back in game) •• “GLICEA – ODDAJ DŁONIE W DOBRE RĘCE” (GLICEA – leave your palms in good hands) •• “ŻYJ Z VIGOREM” – (Live with VIGOUR) Pharmaceutical companies frequently seek trademark registration for slogans that are used in advertising campaigns. Such registration guarantees better protection in case one has to prove one’s rights against unfair competition. As the above examples show, a slogan is usually registered together with the name of a medical preparation and performs two functions: it promotes the name of the preparation and
If slogans were used in foreign languages, they would not be
allows it to fulfill the statutory requirement of distinguishing the goods of
remembered so easily, or would not be understood at all, and consequen-
one undertaking from those of others. On the other hand, a slogan by
tly would fail to build a conceptual bridge between a medical product and
itself, as a descriptive combination of simple words, could be regarded as
a catchphrase. Yet, there are still slogans in foreign languages registered
non-registrable, because as such it would not allow an average customer
under the Madrid Agreement as international trademarks extending to
to identify the goods with a particular undertaking.
Poland, or Community Trademarks. They are usually simple English
Some slogans are regarded as creative works and are protected under
expressions such as “The pleasure of breathing,” “Hours of undisturbed
the Copyright Law. However, due to a relatively low level of creativity, it is
sleep,” “Protecting tomorrow…today,” “The power to move you,” or some
frequently a matter of discussion whether a slogan can be regarded as a
more complicated based on a specific play on words: “It needn’t be hell
creative work. As set forth under the Copyright Law, the subject matter of
with NICOTINELL,” or “Lose the smoke. Keep the fire.”
copyright is any expression of creative activity having individual character
It seems that the stylistic sophistication of a slogan in English is
and manifested in any material form, regardless of the value, intended
irrelevant from the perspective of a Polish customer. Short simple slogans
purpose and manner of expression thereof. According to the doctrine,
understood by most of customers regardless of the knowledge of English,
slogans are perceived as “borderline category of intellectual creativity,”
such as “No more tears,” might be quite effective. However, more inventive
and as such must be analyzed individually in order to determine whether
and complicated phrases, such as “No line. They might do time” in
they can be regarded as creative works. The court case law is not uniform
respect of pharmaceutical products, would not be understood by ordinary
in this respect. Therefore, it seems justified to apply for registration of
Polish customers.
slogans and advertising catchphrases as trademarks, in spite of the fact
In general, using a foreign expression as a key slogan in an advertising
that at the same time they are regarded as personal assets in the meaning
campaign for a pharmaceutical product in Poland would rather be a risky
of the Civil Code, and unauthorized use thereof could be regarded as an
business and might not bring the desired results. It seems that protecting
act of unfair competition.
English slogans in Poland for medicines is more determined by the need
The protection of slogans as trademarks under the Law on Industrial
to protect the translation itself, rather than a real need to use them on the
Property is unquestionable and seems to be the most effective. The owner
Polish market, as it is in case of trademarks registered in both language
enjoying the exclusive right can use even a short slogan such as already
versions:
registered “OTRIVIN. PRZYJEMNOŚĆ ODDYCHANIA” (OTRIVIN. The
“COLDREX MAXGRIP STRONGER THAN COLD AND FLU”
pleasure of breathing), or “PROCTO-GLYVENOL, KOI I GOI” (PROCTO-
“COLDREX MAXGRIP SILNIEJSZY OD PRZEZIĘBIENIA I GRYPY”
-GLYVENOL, it’s comforting and healing). Slogans are usually registered as national trademarks in native language, which is logical, as they must be understood by customers and
It must be mentioned that trademarks in a foreign language, which are not used in Poland, become vulnerable to lapse due to non-use. If an advertising campaign of a pharmaceutical product is based on an
accepted in terms of culture and mentality. Slogans used in advertising
original slogan, customers will quickly remember it and make appropriate
are frequently a play on words, or are based on idioms which, if translated
associations between the product and its manufacturer. Therefore, in
into other languages, lose their impact, e.g. “INNE TAK NIE POTRAFIĄ”
order to obtain broader protection against infringement, the parties
(This is the only one that can do it the right way), “ALFARIN – WARTO
launching a product onto the market and conducting an advertising
MIEĆ W NOSIE” (ALFARIN – you don’t care for it, but it cares for your
campaign are recommended to register their slogans as trademarks, so
nose), or “METEO – ROZCHMURZ SIĘ” (METEO – Brighten up).
that they can effectively enforce their rights if the need arises.
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1/2011
40 | production
Disintegrators – used in tablets Effectiveness testing. Part I
Jerzy Lasota FARMASERWIS
Let us consider the work of a technologist whose task is to design tablets with a short disintegration time. Even if he possesses a great deal of knowledge about available excipients and the process of disintegration itself, it will not be easy for him to choose between the numerous products on offer from different firms. We describe here a proposed experiment to determine the effectiveness of the action of selected disintegrators.
The topic is not an easy one, and is extremely vast, even though it
In the first of these cases, substances are added to the tablet to slow
concerns only a narrow set of excipients used in tablet technology.
down disintegration, thus producing a release profile, which is carefully
Multiple simplifications are applied here, and many related topics are
examined during the production process using expensive and complex
not addressed, the aim being to present only the information which is
apparatus, in tests lasting for many hours. In the other cases, where the
needed in order to perform partial but significant tests. This may prove
tablet is required to disintegrate rapidly, tests can be performed with
to be a contribution to broader-ranging work on evaluating the useful-
relatively simple equipment (Figure 1). It is this type of testing that we
ness of various groups of substances playing a structural role
shall consider here.
in the design of tablets.
Some theory Overview The medicine contained in a tablet needs to be released from the
Both slowing and acceleration of tablet disintegration are subjects on which a great deal of knowledge has been expounded in scientific
tablet in order to produce a therapeutic effect. Release may take place
works over many years. One of these is the doctoral thesis “Testing the
in any of the following ways:
Expandability of Tablet Disintegrators”, written by Feliks Modrzejewski and
•• deliberately slowed, perhaps controlled, i.e. in precisely defined
Lidaiia Wochna at Łódź Medical University in 1965. This work contains the
doses at set time intervals – for the convenience of the patient,
classification given in Figure 2. Expanding substances generally absorb
who can take such a tablet just once a day instead of multiple times;
water rather than dissolve in it, and the growth in volume results from the
•• medium fast, when the only requirement to be met is that disinte-
action of capillary forces. The strength of these forces is illustrated by the
gration time must be less than 15 minutes (this applies to the great
example of a wooden wedge forced into
majority of tablets produced);
a crack in a large rock, which swells so much when water is poured onto
•• fast, where the disintegration time is shorter than 3 minutes (Fast Disintegrating Tablets); •• super fast, up to 30 seconds, for tablets that disintegrate immediately in the mouth, called ODT (Oral Disintegrating Tablets).
1/2011
it that it can break the rock. Expansion may also have side effects in the form of gelatinization, which in turn may slow down the disintegration of tablets, as pharmacists sometimes discover and as this author has had occasion to observe when analysing certain industrial formulas. This
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41
means that the tests proposed here, serving the goal of optimization
Fig. 1.
and precise observation, take on an even greater importance. Looking ahead somewhat, we should emphasize at this stage that the results of disintegration or gelatinization appear or vanish depending on the forces used to form the tablet, including those produced by initial pressure. Apart from expansion, another factor causing disintegration (in other words, destruction of the structure of a tablet) is the straightening out of fibres which were previously tightly packed and highly twisted. An example is the case of cross-linked polyvinylpyrrolidone. This, like croscarmellose sodium and sodium starch glycolate, is among the so-called super disintegrators. The aim of our tests will be to determine how “super” they are. Selected products were used in our tests (Figure 3); the reader may extend this list. Any pharmaceutical technologist or representative of a substance manufacturer may send a sample (c. 30 g) for free testing and possible publication of the results in Part II of this article.
Some practical considerations Are certain disintegrators decidedly better or worse than others? We will answer this question only when we create our own ranking of
Past Pastclassification classificationofofdisintegrators disintegrators
the available substances. When we are designing a formula for fast
(From (From doctoral doctoral thesis thesis of Feliks of Feliks Modrzejewski Modrzejewski andand Lidaiia Lidaiia Wochna. Wochna. "Testing "Testing thethe Expandability Expandability of Tablet of Tablet Disintegrators". Disintegrators". Appl. Appl. Pharm. Pharm. Dept., Dept., Łódź Łódź Med. Med. Univ., Univ., 1965) 1965)
disintegrating tablets, two questions inevitably arise:
No.No.
Substance Substance name name
%% expansion expansion
•• What substance should be used in this particular formula?
Albedo orange orange peel peel 1.1. Albedo
300 300
•• In what quantity will it be most effective?
Natural sponge sponge 2.2. Natural
147 147
Veegum (magnesium (magnesium aluminium aluminium silicate) silicate) 3.3. Veegum
124 124
Formaldehyde casein casein obtained obtained from from milk milk 4.4. Formaldehyde
8686
Formaldehyde gelatin gelatin 5.5. Formaldehyde
7777
Bentonite 6.6. Bentonite
6666
Formaldehyde casein casein obtained obtained from from cheese cheese 7.7. Formaldehyde
4747
Cellulose 8.8. Cellulose
3333
Potato starch starch 9.9. Potato
2929
Certain general observations can be stated just from basic practical experience with disintegrators: •• some of them are easy to overdose, causing undesirable gelatinization; •• their action usually depends on the hardness of the tablet, and thus most often on the crushing force applied during production (and we should be aware of the importance of the fact that this may mean two forces rather than one); •• the use of a disintegrator sometimes reduces the tablet’s hardness, and the question therefore arises as to what quantity of the
Fig. 2.
Maize starch starch 10. 10.Maize
66
Wheat starch starch 11. 11.Wheat
33
disintegrator should be expected to start reducing cohesion; •• sometimes a small quantity of disintegrator is almost as effective as a large quantity, and the question then arises as to where the limits lie and what the optimum quantity is; •• many substances (particularly starches) perform other functions in tablets than merely that of a disintegrator. How can we individually obtain and compare their features?
Substances Substancesselected selectedfor fortesting: testing: No. No.
Chemical Chemical name name
Croscarmellose Croscarmellose 1. 1. sodium sodium Cross-linked Cross-linked polyvinylpyrrolidone polyvinylpyrrolidone
2. 2.
Commercial Commercial name name Manufacturer Manufacturer
Ac-Di-Sol Ac-Di-Sol
FMC FMC
Polyplasdone Polyplasdone ISP ISP XLXL
Fig. 3.
Intended Intended use use
disintegrator disintegrator disintegrator disintegrator binder, binder,
Partially Partially pregelatinized pregelatinized lubricant, lubricant, Starch Starch 1500 1500 Colorcon Colorcon flow flow maize maize starch starch
3. 3.
A partial answer can be given to these questions straight away, which does not yet explain anything, but is nonetheless very important. This is that everything depends on the particular formula. Hence the author’s advice and warning to treat the information given here as an example of a testing method, not as a set of ready-to-apply results. No recipe should be accepted uncritically if it cannot be verified in relation to the formula currently being designed. To end our list of observations we state the most important of them, irrespective of all other factors: the effectiveness of a disintegrator in a tablet is not linearly proportional
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improver etc. improver etc.
Sodium Sodium starch starch glycolate glycolate
Primojel Primojel
DMV DMV
disintegrator disintegrator
5. 5.
Reduced Reduced moisture moisture potato potato starch starch
Perfectamyl Perfectamyl DMV DMV D6D6 PHPH
6. 6.Pregelatinized Pregelatinized starch starch
Prejel Prejel PA5 PA5 PHPH
DMV DMV
filler, filler, binder, binder, disintegratio disintegratio n improver n improver forfor wet wet granulation granulation and direct and direct tabl. tabl.
Vivastar Vivastar PP
JRS JRS
4. 4.
Sodium Sodium starch starch glycolate glycolate
7. 7.
disintegrator disintegrator
Substances Substances which which are are not not disintegrators disintegrators will will not not bebe required required to to have have particular particular disintegration disintegration properties, properties, but but it is it is still still worth worth comparing comparing and and evaluating evaluating them. them. It It may may often often bebe the the case case that that the the mild mild expansion expansion of of starch starch is is sufficient sufficient in in the the formula formula being being designed. designed. The The above above listlist may may bebe extended extended to to include include substances substances proposed proposed byby the the reader. reader.
1/2011
42 | production •• Uniform and relatively non-violent disintegration involving the
Parteck M 100 + MgSt. used as a base
Fig. 4.
rinsing off of successive layers, in order to ensure repeatability of
Tablet Ø10R13 0.356g 30 25
Kp Hardness Kp Eject. force min. Dis. time
20
3.0%
15 10
measurements.
The actual time of disintegration was rescaled for better observation.
•• Heaviness, to prevent the tablet from floating in water, and thus
5
make it possible to work without using weights, which hamper
0 0
10
20
30
40
30
Parteck M100 + 2%MgSt
25 20
0.5%
10
25
Pressure
5
0
10
20
30
4.0%
15 10
40
5
0
10
20
30
40
30 25
30
20
25
1.0%
10
20
5.0%
15
5
10
0 0
10
20
30
5
40
0 0
10
20
30
40
30 30
25
25
20
1.5%
15 10
20
10.0%
15 10
5
0
10
20
30
Serie1 Serie2 Serie3 Serie4 Serie5 Serie6 Serie7 Serie8 Serie9 Serie10 Serie11 Serie12 Serie13 Serie14 Serie15
9 8 7 6 5 4
40 0 0
30
30
25
25
20
20
2.0%
15 10
10
20
30
40
15.0%
10 5 0
0 0
10
20
30
0
40
2
10
20
30
40
pressures used in making the tablets. •• Good reaction to the presence of disintegrators, in order to ensure adequate differentiation of the measurement results. In order not to tire the reader with the ins-and-outs of seeking a to the end result (Figure 4). It can be seen that Parteck containing c.
1
15
5
•• The disintegration time should not be heavily dependent on the
substance that meets the above requirements, we can move straight
3
5
0
11 10
0
15
observation.
20
kN
0
Disintegration time [minutes]
15
12
30
0 0
10
20
30
Pressure force [kN]
40
2% magnesium stearate continues to demonstrate good cohesion (which remains at a satisfactory level even up to content levels of as much as 10%), as well as low dependence of disintegration time
Fig. 5.
No.
1 2
% disint. repet.
4.29 5.22
1.5 0.9
0.6
2.11 3.45 4.02 4.52
4.50
0.7
for those laboratory machines in which the values of the pressures,
3.47
2.2
being dependent on the filling of the matrix, are only approximations
2.58
2.2
to the required values. This applies in the case of the popular rotary
3.57
0.4
Once we have an appropriate substance, we can begin the tests,
2.57
0.6
which initially were to involve the use of only one pressure: 30 kN. Of
2.51
0.0
2.44
1.2
2.33
1.5
2.16
2.9
2.22
1.4
2.21
5.0
1.39 3.13 3.42 4.31
4
1.0
1.20 3.02 3.39 4.17
1.5
4.13 2.36 3.17 3.58
6
2.0
0.51 2.17 2.56 3.37
7
2.5
0.50 2.12 2.51 3.25
3.0
0.40 2.04 2.42 3.18
5.0
0.46 1.52 2.31 2.52
10
0.39 1.32 2.12 2.38
15
0.56 1.42 2.24 2.48
20
1.01 1.37 2.14 2.36
9 10 11 12
on pressures from 20 kN upwards. Hence for the pressures of 20,
0.4
0.8
8
Control of the method’s resolution and measurement error estimation
1.40 4.20 4.25 5.19
3
5
%
30 and 40 kN used in this experiment, there is virtually no change in disintegration time. This low level of dependence is important
machines.
course, that would have been easier, but it was decided to extend the
The table shows disintegration times for pressures of 10, 20, 30 and 40 kN. For selected tablets the tests were repeated (4th column) to estimate the error.
to its quantity. Even this one issue is significant enough that it is worth spending a little time considering it in more detail. And so – to work!
The fundamental stage – preparing for the tests The plan of action is simple. Some substance or formula must be taken and used in all the tests as a base to which different quantities of different disintegrators are added, before measuring the disintegration times for the various tablets. However it is not easy to find such a substance. The tablet should not disintegrate violently into many small parts, one of which sometimes remains for a long time on the grid of the apparatus. A symptom to which we do not pay attention during routine tests (we are more interested in meeting time deadlines) here interferes with the repeatability of measurements and makes it impossible to observe subtle differences. There are more requirements which a base substance should meet: •• Quite a long disintegration time, within 3/4 of the measurement range, i.e. approximately 10 minutes. A longer disintegration time will just increase the duration of the whole experiment, while too short a time will make it difficult to observe changes.
1/2011
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production | 43 measurements over similar ranges, namely 10 kN lower and 10 kN
results for the graph, while one was made as a control (for arbitrary
higher. During preparations (Figure 5) some quite interesting, even
pressure; right-hand column of the table in Figure 5), and the differences
counter-intuitive, results were noted for the lower ranges, and so it was
in the results were calculated. The greatest deviation was recorded
decided also to include pressures of 10 kN. Hence finally the tested
in the last row of the table, where the times obtained (134 s and 141
tablets were made using pressures of 10, 20, 30 and 40 kN. Sometimes,
s) give a difference of 4.96%. For the remaining 12 measurements
out of interest, a still smaller pressure of 5 kN was used as well.
these differences range from zero to 2.9%. The smallest distinguished
As regards the analysed values of the content of tested substance relative to the base, the following sequence of percentages was used: 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1.0%, 2.0%, 5.0%, 10% and
measurement unit was basically 2 s, as the basket of the apparatus moves with a frequency of 0.5 Hz, so one cycle lasts for two seconds. The selected base substance is shown in Figure 6, which contains
20%. Sometimes, depending on free space and expected results,
its full mechanical characteristics. It remains to prepare suitable data
values of 30% and even 50% were also included. In some cases,
acquisition sheets, for which Excel is naturally used. The first is a
depending on observation of the graphs and the free spaces appearing
traditional formula design worksheet, which though not fully exploited,
there, the sequence was made more dense with the addition of interme-
is nonetheless useful (Figure 7, left). Quite important is the vertical pla-
diate values, in order to achieve confidence as to the resolution of the
cement on the sheet of around 20 modules, like the four shown, so as
method. For the case shown in Figure 5, the values which were inserted
to be able just to scroll vertically without switching between sheets, as
and shown on the graph correspond to rows 1–3, 5, 7, 8 and 11 in the
this is much more convenient. The purpose of the second sheet (Figure
table. Of course the resolution is significantly affected by the nature of
7, right) is to discreetly “steal” data from the first sheet, convert seconds
the changes, which are non-linear (significant accumulation of results
into hundredths of a minute, and draw the graph. The third sheet (Figure
in the lower part of the graph), and moreover the analysed dependence
8) takes data from the second sheet and performs the calculation T1-T2/
of disintegration time on substance content is not a monotone function:
T1*100, which computes the percentage by which the disintegration time
it reaches an extremum and then increases again (the lines at the
decreased for the given content and pressures. This is the final result of
bottom of the graph overlap). However, within a range of small values of
our tests: the profile of the effectiveness of the tested disintegrator.
disintegrator content (in this case up to 2%) the resulting functions are
Mechanical characteristics of the base substance
transparent and logical, and significantly distant from each other, which implies that the adopted method has a good resolution. The following method was used to estimate measurement errors. From each weighed batch made for five tablets, four were assigned
37
Parteck
Sifting analysis of product:
Parteck M 100 (Mannitol)
MERCK
19.01.2011 Magnifications from sieves (with mesh sizes given): 0.0 0.1 0.2
weigh sieve with content, then
0.5mm
minus sign
[mm]
1.5 0.7 0.4 0.2 0.1 0.0
[g]
0.000 0.000 0.040 0.172 0.550 4.124 4.886
Disintegrators Purpose : FARMASERWIS
Remarks :
19.01.2011
Results:
%
] [% e v ie s n o g n i n i a m e r
0.0 0.0 0.8 3.5
11.3
11.3
3.5
84.4
0.0
0.1
0.2
0.8
0.0
0.0
0.4
0.7
1.5
mesh size [mm]
100.0
Test the base with small quantity of disintegrator
0.354
First find thickness for T10, then clean matrix and full tests: T2...T40.T40...T2.
4.97
See graph. Matrix is clean after completion of test..
1. Base (Parteck M100 + 2%MgSt) 2. Vivastar P 3. 4. 5. 6. There being more of the substance, a matrix rubbing test was performed to show the full characteristics of the substance...
84.4
weigh empty and record result without
0.4
sieve on sieve
38
Fig. 6.
50 x ?
99.8 mg 0.2 mg
99.8 %
mg
0.0 %
mg
0.0 %
mg
0.0 %
mg
0.0 %
mg
0.0 %
0.2 %
mg
0.0 %
100.0 mg
100.0 %
0.356
Weight [g] tabl. ?10R13 for thickn. 5mm when 10kN: 30
4.990 g * 0.356 ? 0.010 g * Force Main Force 2 press. 1 0.000 g 0.000 g daN kN daN 2.4 2 2.9 0.000 g 4.4 5 4.0 0.000 g 7.3 10 6.3 0.000 g 0.000 g 10.4 20 8.9 5.000 g 12.5 30 11.8 11.1
40
8.1
?
?
Thick- Hard- Disint. ness ness time mm
daN
5.8 5.3 5.0 4.7 4.5 4.4
2.9 4.2 8.2 18.0 27.0 29.0
min
0 0 5 6 6 7
25 20 15 10 5 0 0
10
Crush: 23.6 %
20
30
kN 40
Tablettability: 2.15
Test 38 showed how the substance reacts to pressure. A matrix rubbing test was also performed: the first 6 tablets were prepared with increasing pressures, and the next 6 (intended for disintegration) with decreasing pressures. Hysteresis between the grey curve (injection force 1) and the green curve (ejection force 2) indicates the tendency to rub off. Here it is minimal.
The tested tablets were made using an ELTAB gravitational machine, but thanks to the suitably chosen base substance, which is not very sensitive to pressure differences, a rotary machine can be used instead. In that case, however, the graph data will always contain two components – pressure and time – since the pressures will not be known in advance, but only after the tablet has been formed. The choice of tablet mass, 0.356 g, results from the requirement applicable when measuring forces of ejection (for example): that a tablet pressed with a force of 10 kN should have a thickness of 5±0.1 mm. In this test no such measurements are performed, but for obvious reasons all tablets should be of uniform weight (to an accuracy of 0.002g), and hence batches should be weighed out individually.
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44 | production the results. After completing the tests it may prove necessary to
Fig. 7.
adjust the graphs, e.g. by using different magnifications on the last worksheet, or deleting unused cells containing redundant data which deform the graph. During the tests the worksheet with the graph can be kept on display alongside the basic one, as shown in Figure 7. It is then possible to densify the graph as you go along, which is very interesting and gives an immediate idea about the changes taking place, in a way which is not possible with numbers alone. Interpreting the final graph, we note a small but constantly uniform difference between the lines representing the pressures – this is the effect of the dependence of disintegration time on pressure. Relative to the pink line (20 kN) these are deviations by just a few percent, as would be expected from the substance, given the small dependence of disintegration time on pressure as has already been discussed (Figures 4 and 6). The blue line (10 kN) is already in the range of pressures for which the substance behaves irrationally; we shall return to this subject in Part II. Particularly as we are witnesses to a strange phenomenon: for certain pressures and certain values of content of disintegrator the disintegration times not only fail to
Fig. 8.
decrease, but actually increase! Negative values have been omitted from the graphs for greater clarity, but on the last magnification it can clearly be seen that the curves go below zero. To end with, the most important point. It can easily be seen from the graph that the extremum of all the functions lies at 10% disintegrator content. However, values close to that extremum, with a shortening of disintegration time by approximately 70%, are attained for disintegrator content values of just 0.5–1%. It is even likely that a quantity of 0.6% (maybe 0.7% – this can now be easily checked) acts just the same as 1%. This is all practically already known, apparently nothing new – but with other substances even more interesting things come up. In each case, the graph produced indicates the places which should be subjected to more thorough testing. We can now see for ourselves how unprofitable it is to increase the content from 1% to 2% or more, for example. In our case nothing happens either positively or negatively, but might it not happen that the cohesion of the whole tablet is reduced? If so, for what content of disintegrator will that effect be noticeable? Of course, this can also be tested, and very precisely.
Conclusion to Part I Ahead of any summing up, it is necessary to recall that any specific values given above are correct only for the formula for which the test From observations made during testing of disintegration time, it should be noted that the use of weights may cause a shortening of di-
was performed. Visualization of processes is always a good way of getting to know
sintegration times, which is proportional for all tablets. Without weights
them better. A similar method can be used to investigate the effect
– as was deliberately planned – when the basket moved downwards the
of various substances on, for example, the hardness of a tablet or
tablets rose up to approximately 1/4–1/3 of an amplitude.
force of ejection from the matrix. These are routine actions during the design process. For difficult formulas which cause problems during
The tests and interpretation of results The tests themselves simply involve weighing out 2-gram batches
production, the possibility of optimizing the composition makes things much easier. In tests, the deliberate exaggeration of parameter values
according to the records (confirmed on the worksheet), forming
outside their usable range is done for a particular purpose. Please
tablets, observing the disintegration in the apparatus, and recording
look out for the continuation of this article next quarter.
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46 | production
The importance of print inspection Marcin Weksler MEDsynC Sp. j.
When Johannes Gutenberg invented the first complete printing system in 1439, it had a substantial impact. By 1620, the philosopher Francis Bacon wrote that typographical printing „changed the whole face and state of things throughout the world“. In today‘s world, printed goods are a key element of a plethora of everyday items: printed barcodes are scanned for an easier and faster check-out procedure.
High quality perfumes are presented in attractive covering boxes to
that might appear on one of your printed goods, is fluent in Braille and
reflect the brand image and enhance the value of the product itself.
has an eye for even the smallest displacement in the layout. All you
Folded leaflets present important information on medication, and Braille
need is a short introduction for your employees, and a user-friendly
embossing ensures that the visually impaired are able to identify what
application will perform the basic steps of scanning, inspection and
they are taking.
report generation all by itself. An important fact is that with most system
The print industry has rapidly changed in recent last decades. Tech-
on the market, you have the freedom of choice where you would like
nological progress has enabled substantial new quality standards to
to perform the inspection. That way, you can determine what level of
be introduced for each step of the printing process. Printing companies
security you need.
are fully aware that meeting the customer needs by producing products of high print quality at competitive prices is the best ally in ensuring the long-term survival in this ever-changing environment. Quality Control Officers in pharmaceutical companies know that the strong regulation of
The Pharmaceutical Industry – a world of strict regulations In particular, the highly competitive pharmaceutical industry relies on
their market demands flawless design and production of items such as
print inspection systems. The daily business of the companies working
patient information leaflets or Braille embossing. Many wonder how to
in this field is strictly regulated by the law. In no other area are mistakes
best meet these demands. Modern print inspection systems based on
less acceptable as in the pharmaceutical market. Patient safety is of
the latest pattern recognition technology offer the perfect solution. The
the utmost importance and costly callbacks due to mistakes on patient
best of their class have been developed in close cooperation with actual
leaflets are as fatal as problems with the medication itself. Therefore,
users with a strong emphasis on reliability, ease of use and conforman-
incoming quality control is crucial. The folding carton of an arbitrary
ce to applicable ISO, cGMP, GAMP5, and CFR regulations.
medication, for example, is a complex combination of various functions.
Istead of manual quality control for printed items, customers are
Whereas in the past, it only to protect the actual goods from transport
now able to compare it against an authorised PDF. It is possible to
during transport, it has now many more functions. Transport safety is
detect a multitude of mistakes such as missing letter parts, filled-in
still an issue, but marketing, technical evolution and regulatory affairs
letters, missing ink, colour deviations or smudges within seconds. One
have placed other topics on top of the priority list.
can even detect mistakes that stem from pre-press. Missing accents,
Brand image. One of these topics is for the box to carry colours
wrong character spacing, changed font or incorrect font weight are
and graphic elements specified by the company‘s corporate identity.
among those mistakes that might not be easily detected when merely
Together, they create the unique appearance that makes an important
looking at a sample. Using an automated inspection system ensures
part of the brand image. A wrong colour in the logo or a misplaced
finding mistakes - all of them. The inspection is objective and repeatable
graphical element may even make a customer hesitate. It might lead
- as often as you need. The inspection system speaks every language
to the suspicion that the package in question is not original because it
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47
differs from the look the consumers knows and trusts. Imagine all the
Braille. This small word holds so much importance nowadays.
money carefully invested in building a brand image to be spent in vain.
The new CEN-norm has been in effect since autumn 2010 and
Unfortunately, those types of mistakes regularly occur while re-working
focuses strongly on the height of Braille points. Many companies
the customer PDF for print. (during RIP?!)
are now thinking about safe methods of ensuring that the demands
Barcode. When in the shops, you would not want your product to
of the norm are met by their products. It requires working out
be a nuisance to the staff at the POS. Think of an OTC product that
action standards in SOPs form i application methods of Braille
has a barcode that only works in 1 out of 3 cases, leaving the staff to
quality isnpection. It applies not only to Braille transcryption, but
type in endless number combinations 2/3 of the time. How great is
also height of the point on the packaging. Inspection systems
the possibility that they would recommend a competitive product with
allow to check Braille quality in comfortable, safe and repeatable
working barcode when the next customer asks? Therefore, make sure
manner on the packaging and are ready solution for application
that whatever barcode you have on your box up is correct and well
and implementation with existing quality control system in
readable to ensure a reliable and comfortable check-out.
a pharma company.
Anti-counterfeiting. Another function that unfortunately has to
This certainly is only a handful of examples of where mistakes
be taken into consideration is the need to protect ones goods against
may occur after you submitted your approved PDF to your printer until
product piracy. Anti-counterfeit is a buzz phrase that almost always
you get a finished product back for IQ. The question should not be
pops up these days. Many companies use data matrix code in order to
whether you need a print inspection system, but rather when you will
take measure against illegal drug copying. The code is used in various
start using it. Your nerves will thank you for it!
steps from production to actual POS. It goes without saying that what applies for the usual barcode applies for the data matrix code as well: it can only be of use when it is correctly displayed. Make sure the inspection system you want to buy is up to the task!
Finding the right inspection system. When looking for a print inspection system, a couple of question might help to find the right one: •• Has the vendor of the system experience in the pharmaceutical industry? •• Can the system be validated in the pharmaceutical environment? •• Is the system able to inspect various types of packaging items such as folded leaflets, folding cartons and labels? •• Is the system able to read and inspect braille according to the new CEN-norm? •• Can data matrix code be inspected according to ISO 15415? •• Is the system able to inspect barcodes according to ISO 15416? •• Is the system able to verify barcode quality according to ISO 15426-1? •• Is the system able to inspect artwork, Braille, barcodes and datamatrix in one inspection run or will you lose time because you have to perform more than one inspection run?
Examples of mistakes found with print inspection:
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48 | production
The new EU GMP Annex 11 for Computerised Systems Danilo Neri
In January 2011, the European Medicines Agency (EMA) has issued the new version of the GMP Annex 11, which sets forth the regulatory framework for the management of Computerised Systems in a GMP environment. This update has also implied a number of important changes to the GMP chapter 4 related to the Documentation.
These rules, planned to be effective as from end of June 2011, are
The final version of the new Annex 11 has confirmed most of the
expected to become the key Regulatory reference for the management
requirements included in the draft version issued on April 2008 which
of Computer System and Electronic data across the Europe.
has triggered a high volume of comments from the pharmaceutical
According to the EMA, the update of Annex 11 has been initiated
industry. Based upon these comments, the Agency has removed some
by the EMA due to the increased use of Computer Systems for the
of the requirements which were more focused on the method to reach
execution of Regulated processes and due to the increasing Regulatory
compliance rather than on the expectations of the Agency.
exposures observed within the inspections.
Some observers consider the combination of new EU Annex 11 and Chapter 4 as the European answer to the corresponding famous US rule 21 CFR Part 11 related to Electronic Records and Electronic Signatures. This is partly true as these new European regulations address the
Author short bio Danilo Neri Degree in Physics at the University „La Sapienza” of Rome, PhD
requirements of the entire life cycle of a Computerised System defining as a rule a number of recommendations, which were so far limited to the relevant international guidelines issued by the GAMP forum and PIC/S. In addition, while the US 21 CFR Part 11 has triggered a number of interpretation schemes due to controversial requirements, the EU Annex
in Electronic Engineering at the University “Roma Tre”, Rome. He has
11 strictly identifies the expectations of an inspector in case a regulated
been working as Senior Validation Consultant for Motherwell Information
process is executed through a Computerised System.
Systems, Milan. Since 1999 he has been working for PQE as Validation
The new Annex 11 is still built upon the fundamental statement
Project Manager with expertise on Computer System Validation and
included in the previous version, which requires that where a compute-
compliance to 21 CFR Part 11 and EU GMP Annex 11. In 2003, he
rised system replaces a manual operation, there should be no resultant
obtained the PDA certificate as Auditor of Computer Products Suppliers.
decrease in product quality, process control or quality assurance. However, in addition, the principles of the new version requires also that there should be no increase in the overall risk of the process.
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49
That is due to fact the Annex 11 actually implements in the compu-
The expectations for the Risk-based Validation process are further
terised pharmaceutical environment the Risk Management concepts
detailed in the new Annex 11: the Validation life cycle is expected to be
addressed by the guideline Q9 Quality Risk Management issued on
established upon the User Requirements, now explicitly addressed by
2006 by the International Conference on Harmonisation (ICH), which
the rule, and the related traceability against the system specifications
includes the regulatory authorities and pharmaceutical industry of
and test scripts. The testing effort (again, Risk-based) shall not be
Europe, Japan and the US.
limited to the verification of the sunny day scenarios (i.e. normal conditions) but it shall also address process parameters limits, data
Risk management is requested to be applied throughout the lifecycle of the computerised system taking into account patient safety, data integrity and product quality. The requirement for risk-based decisions are distributed throughout
limits and error handling. A crucial new requirement set forth by the incoming rule is the qualification of the IT infrastructure where Computerised Systems reside: the IT components (e.g. servers, clients, network) are
the whole new regulation. The validation effort and the level of data
expected to be under a state of control in order to minimize risk to
integrity controls shall commensurate with the documented risk associa-
the data integrity.
ted to the process(es) executed through the computerised system. The method for Supplier Assessment, the need for Audit Trail and other key
The new Annex 11 requires that the Computerised Systems used by
requirements are requested to be determined based upon the (docu-
the firm shall be formally listed in an Inventory which shall include the
mented) Risk associated to the system and/or to its functionalities.
regulated process executed through each system.
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50 | production
In addition to the elements above described, the most innovative element brought by the new Annex 11 is the authorization to the use of the Electronic Signatures, which was not even mentioned in the previous version of the rule: the pharmaceutical firms are now allowed to use of Electronic Signatures on documents, reports and records identified in the GMP regulations: this change bridge the most significant gap with the corresponding US rule 21 CFR Part 11. The signature mechanism is required for all those regulated operations for which the GMP rules explicitly require a formal authorization. Particularly, for the Lot Release, which is the most critical operation in the GMP environment, the use of the Electronic Signature is reported Pharmaceutical firms are required to implement a Quality System dedicated to the management of Computerised System oriented to address the following IT-related processes:
as mandatory in order to properly record the release/certification of a batch. Although the requirements related to the Electronic Signatures
•
Validation Policy and Standards
are clearly stated, there is still a grey area in the application of these
•
Change Control and Configuration Management
statements due to different legal requirements currently in place in
•
Security
the EU countries. The equivalence on the legal basis shall be further
•
Periodic Evaluation
clarified by the European Agency.
•
Incident Management
•
Business Continuity
•
Archiving
The changes to the GMP Chapter 4 (related to documentation) have been implemented by the Agency in order to align and
These processes shall be activated for any GMP relevant system
integrate the expectations defined by the new Annex 11. The new
included in the inventory from the Project phase to the Operational one.
Chapter 4 includes a clear identification of the so called Regulated Records, i.e. all the documents and data required to be created and
The measures oriented to routinely ensure the Data Integrity have
adequately retained by the pharmaceutical firms in order to provide
been rebated and enforced: the systems shall include Built-in checks
evidence of the compliance to GMPs. The rule addresses the
for data transmitted through interfaces and Accuracy checks in order
management of these documents either in paper or electronic form,
to minimize the risk to impact the data. The need of these checks has
including the expectations for the hybrid cases (electronic records
been extended also to the migration process usually executed when
manually signed with a handwritten signature). Another important
data are massively transferred from one system to another immediately
element defined by the rule is the determination of the Retention pe-
before the system release.
riod for each Regulated records: in case these records are managed
The Audit Trail is still required to automatically record any change and deletion to the Regulated Records; in addition, the new rule
in electronic format, the retention requirement will imply severe rules in the maintenance of Electronic Records over the years.
requires also the related reason to be documented. Based upon these considerations, the new EU Annex 11 and The qualification of Suppliers and Service Providers is reported
Chapter 4 are expected to raise the compliance bar for the Compute-
as a key element in the new Annex 11: any third parties contracted
rised System since most of the recommendations for System life cycle
to provide, install, configure, integrate, validate, maintain, modify or
have become a Regulatory requirement (i.e. the law). As a consequence
retain a computerised system or related service or for data processing
of these new combined rules, an enforcement of regulatory inspection
are required to be formally assessed and qualified. The results of the
on this topic is expected in order to address the serious weaknesses
Supplier assessment shall be made available to the inspectors: this
in company procedures and processes for the management and use of
means that the System/Supplier selection process shall preventively
computerised systems to the current GMP.
address the risk to commit a poor quality Supplier.
Pharma Quality Europe (PQE) was founded in 1998 and it offers Consultancy and Services in the field of Computer System Validation, Quality Management, Quality Engineering, Technical Qualification and Clinical Trial Management through its Business Units, certified according the UNI EN ISO 9001:2000 Standard. PQE is able to synergistically combine four different disciplines: Quality, Information Technology, Engineering and Pharmaceuticals. Extensive knowledge of Project Management is also a key feature of PQE’s teams, closely linked to a solid understanding of International Regulatory Issues, acquired over many years of experience within the life science industry.
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production | 51
Formation of aerosols during absorption and effects on the design of gas scrubbing systems for chemical and pharmaceutical industries Karlheinz Schaber, Marc Stober GEA Wiegand
During the production of various chemical and pharmaceutical products exhaust gases are produced in the exhaust air systems of reactors, in mixing tanks, preparation tanks, storage tanks and production chambers which might contain large quantities of acid and caustic components, such as for example hydrogen chloride, sulphur dioxide, thionyl chloride, chlorine, ammonia, amines and even dust.
Quantity, concentration and composition of the exhaust gases are
Condensation aerosols are formed in particular in the presence of
subject to strong fluctuations, mainly due to the filling and emptying of
HCl and SO3. A typical reaction aerosol is ammonium chloride (NH4Cl),
reactors and tanks.
forming during the reaction of HCl and NH3. Sublimation aerosols might
In consequence of this situation, exhaust air scrubbing systems have to fulfil special requirements to meet the statutory emission limit values. Caustic and acid corrosive gases are separated above all via absorption processes, i. e. wet scrubbing processes which are described
form, for example, in melting processes. For the subject matter of the present article, however, they are of secondary importance. Tab. 1 shows the particle size range for some aerosols. The indications stem from different sources. The size of condensation aerosol droplets, such as hydrochloric
in the following paragraphs. The following considerations are focused on the problems involved
or sulphuric acid mist, mainly ranges between 0.5 and 2 µm. The
with the formation of aerosols during absorption and their effects on the
particle size of reaction aerosols, such as ammonium chloride, is
design of gas scrubbing systems, taking into consideration the currently
much smaller and can even be smaller than 0.05 µm. The particle
valid emission limit values.
size of aerosols mainly depends on the specific nucleation and coagulation conditions.
Absorption and problems relating to the formation of aerosols Absorption processes can be calculated via common methods, if the respective phase equilibrium and mass transfer coefficients are known.
For condensation aerosols there is a functional connection between droplet size and degree of supersaturation: the droplet size decreases with increasing degree of supersaturation. And contrariwise, with increasing life and increasing particle density,
However, the formation of aerosols represents a difficult problem during
aerosols coagulate to larger particles. However, coagulation processes
absorption.
lasting minutes or hours are of minor importance for technical gas
Aerosols are solid fogs or mist consisting of very small particles. Depending on the way of formation, three types of aerosols can be distinguished:
of seconds. The large spans of particle size ranges shown in tab. 1 can at least
•• condensation aerosols which will be formed if the dew point of a gas mixture is not achieved (droplet mist) •• sublimation aerosols which will be formed if the sublimation point of a gas mixture is not achieved (solid mist) and •• reaction aerosols which will be formed as a result of chemical reactions of acid and caustic components (solid mist)
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partially be explained by different coagulation stages and supersaturation degrees. Aerosols cannot be separated by absorption. Absorption is a process determined by diffusion. In comparison to molecules, diffusion coefficients of aerosol particles are lower by approx. 3 – 7 decimal powers and are therefore too small for technical absorbers.
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52 | production 0,01 [µm]
0,1 0,05
1
10
0,5
5
100 50
Lit.
Aerosole NH4Cl
[13] [14] [11,12]
H2SO4
[13] [14]
HCl
[17]
Flugasche
[13,14]
Tab. 1. Particle sizes of aerosols
The separation of aerosols is only possible with mass or inertia force separators with a high use of energy, or in electric filters. Aerosols can
Aerosol absorbers and separators In the jet scrubber, a mass transfer surface is created by means of
form in two areas:
nozzles which spray the fluid. The water drops coming out of nozzles at
•• in the exhaust air collection system or
a high speed cause an impulse transfer to slower gas stream and thus a
•• during absorption in the absorber
pressure increase. In this way, the jet scrubber can convey the gas flow to be scrubbed without requiring any additional fan. The droplets which
Reaction aerosols will be formed in absorbers if acid or alkaline scrubbing fluids with high partial pressures of the reactive component in the gas phase are used for the chemisorption of caustic or acid gases.
are formed in the scrubbing pipe can be separated in a centrifugal separator which operates according to cyclone principle. The mass transfer surface forming in a column mainly depends on
In this case, there will be a reaction of the caustic and acid components
type and size of the used packing. A good distribution of the scrubbing
in the gas phase and, as a result, a formation of aerosols, for example
liquid on the packing bed is crucial and can be achieved at best with a
the absorption of ammonia in concentrated hydrochloric acid or of
spray nozzle.
sulphur dioxide in ammonia solutions. The formation of these reaction
In the Venturi scrubber, fluid is sprayed into a gas stream accelera-
aerosols, such as NH4Cl can, however, be avoided, if acid and caustic
ted to high speeds (50 – 150 m/s). Due to the high shearing forces the
exhaust air is collected and scrubbed separately.
fluid is dissolved into small drops and thin layers. In this way, a very
With a corresponding process control, the formation of aerosols can be avoided in those cases in which hydrochloric acid is used as scrubbing fluid. Unlike reaction aerosols, the formation of condensation aerosols cannot be avoided. Condensation aerosols will be formed during the
large surface is built within a fraction of a second. Venturi scrubbers are mainly used for dust separation. The average relative speed between gas flow and fluid is the determining factor regarding the formation of dust and aerosol. The high relative speed in a Venturi scrubber results in a high degree
absorption process, if in systems with a clear steam pressure minimum,
of separation for fine dusts and aerosols, such as for example NH4Cl.
the thermal balancing process and the enrichment of the gas phase with
However, these high degrees of separation involve very high pressure
water steam proceeds faster than mass transfer from exhaust gases
drops of 100 – 200 mbar implying high energy consumption values.
into the liquid phase. In case of absorption of hot gases only at the end
In jet scrubbers, at average relative speeds between 10 and 25 m/s
of the saturation process a hardly-to-notice dew point exceeding is
at least condensation aerosols in a grain size range > 1 µm can yet
possible.
be partially separated, whereas columns with packing are completely
In case of absorption of cold exhaust gases (T<80°C) with a heavy load with HCl it should be considered that HCl mists might form in the
inappropriate for the separation of fine particles. When selecting a suitable absorber and separator, not only the
absorbers and that these mists have to be separated again. HCl mist
energy consumption values, but also the partial load behaviour,
droplets contain highly concentrated HCl, which is an outcome of phase
susceptibility against soiling, maintenance expenditures and operational
equilibrium.
reliability play an important role.
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Fig. 1. Gas scrubbing system A for an integrated exhaust air collection system I 1st stage jet scrubber, absorption of HCl, NH3, dust, SOCl2 II 2nd stage jet scrubber, absorption of HCl, SO2 III 3rd stage Venturi scrubber, absorption of SO2, aerosol (NH4Cl, HCl)
The lowest risk of soiling and thus the lowest maintenance expenditures can be achieved with jet scrubbers without packing. In case of fluctuating gas rates, only such Venturi scrubbers can
Two different basic plant designs shall be compared: •• Gas scrubber A for an integrated exhaust air collection system in which dust, SO2, thionyl chlorine (SOCl2), HCI, NH3 and so
be used for the separation of aerosols which can be controlled, i. e. in
also NH4CI aerosols occur at the same time and also have to be
which an automatic displacer ensures uniform pressure losses and thus
separated simultaneously.
uniform degrees of separation for fine particles at varying gas rates. The absorption degree and the dust separation degree of a jet
•• Gas scrubber B for an exhaust air collection system with separation of acid and caustic gases and with direct source exhaust air collec-
scrubber strongly increase with decreasing gas rate. In packing
tion in chemical reactors. Due to the source exhaust air collection,
columns only the degree of absorption increases with decreasing
an additional separation of strongly loaded, almost inert gas free and
gas flow. For the separation of condensation aerosols even high-
slightly loaded gases, is achieved. In this case no NH4CI aerosols
-performance demisters (mist separators) can be used which consist of
occur.
multi-layer, fine fabrics. However, at partial load, the separation capacity of demisters decreases with decreasing inflow speed. GEA Wiegand developed a high-pressure nozzle system using
Fig. 1 represents a simplified flow diagram of gas scrubbing system A. As absorber of hazardous gas, two compact gas scrubbers with
coagulation properties of aerosols in the supersaturated range. With
downstream arranged packing beds were selected. Compact gas scrub-
this arrangement the droplet size of aerosols can be increased so that
bers consist of a cylindrical shell with integrated jet scrubbing pipe. This
with suitable mass or inertia separators, such as a Venturi scrubber, the
design is patented and combines the advantages of jet scrubbers and
separation is possible. The separation capacity of a Venturi scrubber
columns with packing in one unit.
can be kept constant by means of an adjustable cone even under partial
In the first stage, dust, HCl and NH3 are separated and thionyl chlorine (SOCl2) is hydrolysed, i. e. it reacts with water to HCl and SO2.
load operating conditions.
The decomposition of thionyl chlorine in the scrubbing solution results
Comparison of two plant designs for reactor exhaust air systems In this section, the findings on the formation and separation of aerosols as explained above shall be taken into consideration for the design of a plant.
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in a supersaturation with SO2 which then can be discharged again in the waste water system. Therefore, the excessive SO2 has to be removed from the discharged product in a stripping column. The fresh water feed rate is adjusted in such a way that with maximal HCl a solution of max. 5-10% solution will be created. The
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54 | production partial pressure of HCl is yet below the critical level so that in case of occurrence of NH3 no important formation of NH3 aerosols has to be expected. If increased quantities of NH3 occur, fresh acid will be dosed via a pH-value adjustment in order to maintain the neutralization. In the second stage, SO2 is absorbed by caustic soda and at the same time the residual quantity of HCl gas from the first stage will be separated. Fresh caustic is fed via a pH-value control system and the product is discharged via a level control. Subsequently, the product can be oxidized into sodium sulphate in a separate oxidation stage. The third stage is an adjustable high-performance Venturi scrubber which is designed for the separation of NH4Cl aerosols and for the separation of HCl aerosols which formed during the absorption in the 1st and 2nd stage. Photo 1 shows an example of an operating system. Fig. 2 shows the sketch of gas scrubbing system B for a separate exhaust air collection system. The strongly loaded source exhaust air which is almost free of inert gases is scrubbed in separate scrubbers. In this process, HCl can be recovered in a form of hydrochloric acid of 20 â&#x20AC;&#x201C; 30% and NH3 as a solution of 25%. Due to the low portion of inert gas, the reaction heat occurring during absorption cannot be dissipated via evaporation cooling. Therefore, heat exchangers are required (photo. 2). Source exhaust air scrubbers operate discontinuously. Slightly loaded caustic and acid exhaust air is scrubbed in two compact jet scrubbers in above described design. Contrary to the situation in system A, the installed fan has to overcome only the pressure difference of the exhaust air system and of the HCl mist separator (high capacity Photo . 1. Example of an operating system
demister) installed in the acid scrubbing stage.
Fig. 2. Gas scrubbing system B for a separate exhaust air collection system
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production | 55
Photo . 2. Example of a system for source exhaust air scrubbing
For a quantitative comparison of both scrubbing systems, table 2 shows design data, energy consumption data and investment cost for both systems. The main difference between both systems is the fan
of 125 mbar is required, assuming a grain size range between 0.1 to 1 µm. Compared to version B, we can see a significantly higher energy
capacity. In order to reduce the NH4CI aerosols which only occurred in
consumption which corresponds to annual costs of almost € 40 000.
system A to the required value, a Venturi scrubber with a pressure drop
Moreover, the investment costs of system B are much lower although the equipment with three heat exchangers and five absorbers is much
Suction pressure Hazardous substance load
more expensive compared to version A.
-5 mbar Gas inlet
Gas outlet
HCl
100
kg/h
20
mg/Nm³
SO2
175
kg/h
50
mg/Nm³
NH3
100
kg/h
30
mg/Nm³
NH4Cl
50
kg/h
50
mg/Nm³
--------
Urządzenie A
Urządzenie B
This can be explained by the fact that in system A a much more expensive fan is installed with an impeller made of Hastelloy or titanium and that the separator of the Venturi scrubber has to be designed for very high negative pressure. Moreover, in version A expensive sound protection measures are required for the fan. A sound insulation booth with ventilation system is necessary. The comparison of these two versions explicitly is in favour of system B, i. e. for a separate exhaust air collection.
strata ciśnienia wentylatora
125
mbar
-
mbar
różnica ciśnień wentylatora
135
mbar
15
mbar
potrzebna wydajność wentylatora
ca. 65
kW
ca. 6
kW
wydajność pomp
ca. 30
kW
ca. 24
kW
energia elektryczna, suma
95
kW
30
kW
system. However, due to the fact that the exhaust air scrubbing
koszty produkcji, energia
56 525
€/rok 1)
17 850
€/rok 1)
system is considerably more favourable in terms of investment
koszt inwestycji
ca. 700 000
T€ 2)
ca. 550 000
T€ 2)
Tab. 2. Comparison of gas scrubbing system, version A and version B 1) Operation time 8,500 h/year – energy cost 0.07 €/kWh 2) Turn-key system – main material: PP, price basis for 2011
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In terms of the operating cost balance, the possibility of an easy recovery of products such as hydrochloric acid or ammonia is also in favour of version B despite the additional cooling water demand. On the other hand, the costs for a separate exhaust air collection system are of course much higher than the costs for an integrated
costs, these additional costs will amortize after two years of operation at the latest. You will find more information on www.gea-wiegand.de.
1/2011
56 | logistics
Transport of Medicines under Controlled Conditions Anna SĹ&#x201A;aboĹ&#x201E; Director of Key Accounts Pharmalink Sp. z o.o. www.pharmalink.pl
Nowadays, one puts a greater emphasis on the professional transportation of medicines that gives a possibility to evidence the maintenance of proper conditions. It is especially significant in the transportation of thermolabile medicines, in the temperature from 2 to 8oC.
The maintenance of such a narrow temperature range for
There are various methods. The most well-known are: isothermal
a general delivery within the whole period of the transport
foam containers and a transport in a cold chain that is a temperature-
(about 24 hours) is rather difficult. That is why, many companies
-controlled open-load carrying body.
consider the best ways of protection and preservation for the products.
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Thus, let us consider these two options and see what result they may cause. The isothermal containers â&#x20AC;&#x201C; they are usually used for the trans-
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57
port of medicines from 2 to 8oC. They are made of foamed polystyrene.
way. The whole scope of operations undertaken for medicine protection
The walls’ thickness constitutes a crucial aspect of the final choice.
is time-consuming and requires the highest professionalism.
To make sure if the container preserves the required temperature for a certain period of time, one has to make validation. Thanks to validation,
What can an easy solution give us in such situation?
one will manage to choose a proper sort of a container and one will be
The best solution is the transportation in controlled conditions in
able to establish the exact number of the cooling refills. Definitely, the
specialist vehicles with an open-load carrying body, cooled to needed
containers with thicker walls bring more benefit. The thin-wall containers
temperatures. Thanks to such solution, there is no risk of contact be-
are not able to maintain the required temperature for 24 hours, what is
tween the products and frozen refills; we do not have to make numerous
more, they are susceptible to the surrounding temperature, which finally
validations and separate procedures. Another advantage is more free
has an impact on the inner temperature, inside the container.
space of the square footage in the storage. If the packaging
Another issue which accompanies isothermal foamed polystyrene packaging are the refills. The refills need to be frozen appropriately before they will be placed inside each container. Proportionately long-
is non-standard, we are not dependent on their size. However, the most important factor in the cold-chain transport is the maintenance of the highest quality.
-enough freeze gives a chance to maintain demanded temperatures.
The Pharmalink Company is the first company which made an effort
However, there is a danger of over freezing the medicines if the refills
to transport medicines 2-8oC, in the so called “cold chain”. As a result,
are too cold. The contact between the refill of -15oC /-20oC and medicine
Pharmalink is the market leader that provides high standards and
may result in a product damage. It is clearly observable if one puts
security of the transported goods.
a temperature recorder inside the body of the container. The temperature recorder placed next to the refills shows below zero. The additional problem constitutes the type of the transported
All cars are equipped with electronic temperature monitoring. In order to document the transport conditions, the temperature recorder can be attached to fulfill the eventual Client’s request. Numerous
product, namely, its thermal capacity. One has to bear in mind the fact
cold-chain transports that have been realised by Pharmalink prove that
that the temperature of, e.g.: a liquid vaccine will differ from solid state
such way of transportation provides high quality and for the time being
products (for instance, tablets). It seems that all types of products sho-
is the best logistic solution in the pharmaceutical sector.
uld be given different validations and should be packed in an individual
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58 | logistics
Logistics of Pharmacy â&#x20AC;&#x201C; A Challenge for Processes and Ways of Thinking Andrzej Lada-Kubala Damco Poland Sp. z o.o. Part of the A.P. Mollerâ&#x20AC;&#x201C;Maersk Group
In pharmacy, just as in every industry, we deal with a flow of goods, storage and additional services such as creating promotional packages, samples and sets. However, in this case these processes are subject to standards and legal requirements placed on the supply chain.
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59 Before we begin considering the processes and requirements
Own warehouse
Distributor
Logistical Operator
Investment in infrastructure Investment in equipment Necessary to maintain warehouse staff
YES YES
NO NO
Partially NO
YES
NO
NO
Payment only for space used
NO
NO
YES
Payment only for operations carried out Transfer of property rights Necessary to create Back Office departments Incur costs only for resources used Flexibility of product portfolio Services added in GDP standard Services added in GMP standard Incur costs from sales commission Access to fleet and distribution services
NO
NO
YES
NO
YES
NO
YES
NO
NO
themselves, we should decide and choose an appropriate scenario for our logistics, which is by no means easy. Looking at the market, three basic models can be differentiated: Distributor: In this model the responsible entity, manufacturer or importer chooses its partner and transfers practically 100% of logistics operations to him, including sales. In this model the Distributor purchases batches of goods, causing property rights to be transferred to the distributor and all the obligations arising from them to be taken on by him. When deciding to collaborate with a Distributor we have little influence on the processes, level of service or sales level, but our logistics are very simple and limited to organising deliveries and settling with the Distributor. A solution of this kind also allows us not to commit our own financial resources to building up commercial or logistical structures or other auxiliary departments. Collaboration is usually based on settlements of a percentage of the turnover realised by the Distributor. Logistical Operator: It is possible to use the services of a
NO
NO
YES
YES YES NO
NO NO NO
YES YES YES/Option
NO
TAK
NO
NO
Partially
YES
Tab. 1.
specialised logistics operator who will service individual links or larger sections of the supply chain on our behalf. In this model we can take
turnover of pharmaceutical products, and cost optimisation
two roads. The first is supporting our services with the Pharmaceutical
is of secondary importance at most. Legislators have attempted,
Consignment Warehouse owned by the logistics operator. This solution
by additional measures such as a guarantee that paths will
is characterised by very high flexibility, since we only incur costs for
not cross, the necessity to isolate products from one another,
the space taken up. Basing our services solely on the Pharmaceutical
damaged goods zones, quarantines, recycling, entry and exit
Consignment Warehouse limits our distribution opportunities, however.
zones, additional quality control along with registration on entry
The second model is combining our own pharmaceutical warehouse in
and temperature and humidity controls throughout the process,
the logistical operator’s warehouse with the Pharmaceutical Consign-
to make the logistical chain for pharmaceutical products safe
ment Warehouse owned by the operator. This combination allows costs
for the end customer. This idea affects the processes and their
connected with setting up and then maintaining a warehouse to be
costs. Regardless of whether we operate our logistics using our
significantly minimised, while ensuring the full flexibility connected with
own resources, through a Distributor, or if we contract them to
access to the Pharmaceutical Consignment Warehouse.
a logistics operator, we must remember that adhering to
Own logistics: Obviously the most popular solution which can be implemented is to create one’s own pharmaceutical warehouse and
standards and instructions costs money. Money, however, is not everything. Process errors may have a major impact on the
conduct distribution from it. This solution, however, requires significant financial investment, and later costs incurred due to space, equipment and personnel not being 100% used. The table 1 below presents the advantages and disadvantages of the individual solutions. For some time now there has been an observable trend involving outsourcing in pharmacy logistics. More and more businesses are deciding to transfer their services to external companies. It should be remembered, though, that this solution also has its pluses and minuses. Here are a few of them:
What about processes? Servicing pharmacy requires an entirely different approach than for other industries. When deciding to set up a pharmaceutical warehouse or consignment warehouse we must abandon the ‘optimise always and everywhere’ attitude. This approach, although completely natural for logistics, is wrong in this particular case and can lead to serious logistical problems. Analysing the GDP and GMP we see that their aim is to maintain security of
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60 | logistics Advantages of outsourcing
Disadvantages of outsourcing
Optimisation of investment in w infrastructure and equipment By using the services of an operator we minimise the costs connected with renting or building warehouse space and maintaining it at the appropriate size during the ‘season’. Servicing many clients in the consignment warehouse allows the operator to make use of the space and ensure greater flexibility. Similarly, by combining volumes from many projects the operator can achieve better usage of warehouse
Necessity to standardise processes With medium and small projects, the logistical operator will try to adapt our processes as much as possible to the standard which he applies in his operations
equipment such as forklifts and shelving. Minimisation of operational resources and connected costs When passing on services to an operator, there is a chance to reduce human resources necessary to service the warehouse procedures. This cost is
Necessity to create communication between our system and that of the operator
included in the fees and is incurred by the operator, the situation is similar with
The operator usually has his own WMS class system, it is vital to construct EDI
operational costs in logistical processes
communication between the systems.
such as foil, tape, labels, etc. Minimisation of management staff As our operations increase we must appoint more and more staff to manage
Limited access to information
logistics, leading to an increase in costs connected with Head Office. Contract
Since operations are conducted by the operator, we have limited access to
logistics allows these resources to be significantly smaller as we mainly
operational information.
conduct checking procedures. Minimisation of Back Office structures Passing processes on we minimise the resources necessary to maintain
Costs connected with special services
infrastructure and IT tools, accountancy and HR. It should be remembered that
An operator is far less flexible with regard to non-standard operations
when developing our own logistics department, all those departments which
and will expect payment for activities which deviate from the defined standard
are not directly connected with the processes must be equipped with the
of service.
appropriate human resources to maintain continuity of the processes. Costs only incurred for resources used Rates based on movement of goods guarantee that we only incur costs when we make a sale. Our costs are closely connected with revenue, which allows
––––––
improved cash flow. Greater access to the fleet A logistical operator who coordinates transport services for a lot of companies has a far larger number of subcontractors at his disposal, and thus greater
––––––
flexibility than if we had to build up our own portfolio of carriers. Greater business flexibility By deciding to invest in infrastructure and equipment we limit our business flexibility at a time when it is necessary to change our profile or service
––––––
portfolio. Contracts with an operator are medium-term, which increases our possibilities in the event of a change in medium or long-term business strategy Tab. 2.
company’s image or sales, which is why it is important to choose
only a few logistics operators with experience and the necessary
a tried and tested partner who will guarantee the reliability and
knowledge. For some time now the pharmaceutical industry has
repeatability of his processes. We all know how painful it is to
been enjoying great success among logistics companies trying to
learn from our own mistakes, and how time-consuming that is.
start up operations for pharmacy, but the standard and process
In the current market situation, competitors who try to exploit
are not always consistent with GDP requirements, which may
every tiny slip-up by the opposition have no time for experimen-
be a dangerous trap waiting for those who want to economise.
ting and learning. Despite dealing with pharmaceuticals, we
When selecting a partner we should remember that GMP and
should remember that ‘open heart surgery’ always carries
GDP are not there to make life more difficult, but to save lives
a great risk. This state of things means that in Poland there are
and guarantee proper and effective operations. There purpose
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reklama
is not to save money but to guarantee that a company supplying services can provide a safe and tested solution.
What about all-inclusive services? And what if we have to add a leaflet to the packaging? Is every Distributor and Logistical Operator or our own Warehouse able to meet this challenge? Nothing could be simpler – employ a few temps, give them a table and let them put in the leaflets or stick labels on the packaging. This is the right way if we have enough financial resources to recall a product from the market and we can afford the fines and sanctions associated with illegal activities. Unfortunately in the case of pharmacy such mundane procedures as sticking labels on unit packaging or putting in leaflets are treated as production, and carrying out production activities requires production licences, fulfilment of GMP recommendations, and the necessary infrastructure and processes. Slowing down a batch, taking samples from production or validating the tools used in processes is alien to most of us. It is also difficult to
A
n enterprise´s success depends on the cooperation and assumes two things above all: understanding and condidence. Out of house as well as in-house. We work that way! The gradually grown constituency esteems the friendly business relationship, the individual solutions of problems, the distinctive feeling for quality and the high readiness to deliver of our company. Concerning our employees the long lasting periode of employment speaks a clear language. The beginning of our company goes back to the year 1932. Yet, in our opinion experience cannot be measured with sober figures only. Years alone are not sufficient! In addition there must also technical know-how in connection with skilled performances of qualified and motivated employees. And this is the reason why we are realizing partner-like innovative concepts for our reliable partners for more than 70 years now. “Your decision for Heinlein means that you are not buying any closure”. But what is it exactly that our customers are appreciating so much on Heinlein? 1.
find a chemist or qualified person in a standard logistics company, but when servicing the pharmaceutical industry we must meet these requirements. Looking at the logistics market for pharmacy, all-inclusive or complex services are unusual, apart from a few exceptions. The multiplicity of requirements and tighter standards mean that even
2. 3.
large, serious companies have trouble safeguarding transport, storage, additional services and distribution, not to mention such requirements as storage at a temperature of 2-80C, storage of cytostatics, poisons, narcotics, etc …
Is transport also something unusual in the case of pharmacy? It quickly transpires that transport of pharmaceutical products is
4.
5. 6.
governed by its own laws. While in the case of full-vehicle deliveries the problem is smaller, distribution requires appropriate infrastructure. A loading platform for pharmacy must have a loading chamber reported to the Main Pharmaceutical Inspectorate, the chambers must be under
7.
constant supervision by a chemist and the loading process is strictly defined with regard to maximum time. In addition, there is documentation guaranteeing full registration of transportation conditions and several other requirements.
So is it worth servicing the pharmaceutical field?
8.
To summarise, pharmacy is a field which requires relevant knowledge and awareness, a field requiring significantly greater investment than elsewhere, and long-term commitment which involves including pharmaceuticals in medium and long-term strategies. In spite of this, it is an attractive market for a number of reasons – firstly someone has to deliver the products to customers, secondly there will always be a demand for pharmaceutical products regardless of the state of the market, and thirdly loyalty among contractors is much greater than in other industries. An additional plus is the opportunity for self-improvement and to raise the quality of our processes, which can be applied to other projects thus providing a competitive advantage over other companies.
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Heinlein Plastik - Technik GmbH i. A. Peter Meister (VT-11) Vertrieb, sales assistant Tel: ++49 (0) 9 81 / 95 02-25 Fax: ++49 (0) 9 81 / 95 02-50 meister@heinlein-plastik.de www.heinlein-plastik.de Geschäftsführung: Saskia Wellhöfer, Jakob Selnar Sitz der Gesellschaft: Ansbach HRB 434 Industriestraße 7 Eingang Funkenbachstraße D - 91522 Ansbach Postfach 1962 D - 91510 Ansbach
62 | logistics
Electronic management for pharmacy Application of global identifiers and not only medicines – part III Anna Kosmacz-Chodorowska Institute of Logistics and Warehousing - GS1 Polska
In the series presenting the most effective solutions for the pharmaceutical Line of business in the field of e-economics our Readers have already been acquainted with many issues regarding bar-codes and electronic data interchange which are implemented in the whole supply – chain all over the world and in Poland.
To encourage to use these solutions, first we have explained what they
system (formerly EAN.UCC). For this purpose this conditions for the
consists in including the problem of improvement business processes of
producer / operator or the firm representing medicaments of the foreign
manufacturers, wholesalers and pharmacies.
producers and for the distributor – wholesalers and pharmacies – were
We have written how worldwide identifiers of GS1 Global system:
talked over.
•• GTIN for products •• SSCC for logistic units such as products on pallets or in boxes or craters •• GLN – to identify the location of business and individuals. Are the most commonly used by bar-codes, and also in electronic documents like order or electronic invoice.
We have presented how these solutions from America reached
In Poland these conditions are particularly complex, especially due to acquisition by the Ministry of Health (MZ) agency in giving codes for the drugs registered in retail packaging. Since December 1999 and since 2004 Ministry of Health practically the Registration office has been mediating in giving numbers GTIN-13 (up to now called wrongly in the low records of the Ministry of Health as EAN-13 codes). These number
appear on the certificates of the certificates of registrations under the
Europe and from there the whole world, and of course, Poland. We
agreement between the Ministry and the National GS1 Organisation
have also written how dynamic the range of using such solutions in
– the Institute of Logistics and Warehousing (ILiM – GS1 Polska).
the business practices is extending not only in the field of articles of common usage but especially just in the health-market.
ILiM – GS1 Polska analyzing a database of information used in computer since service of the health market found many irregularities.
From the previous publication regarding this cycle Readers also learned that in order to benefit from all these global standards and the most effective solutions, one has to be a member of the GS1 Global
1/2011
Since there are still a lot of misunderstandings concerning this issues – we will explain it once again.
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Explanation the rules of giving codes for pharmaceutical products in Poland In order to clarify such misunderstandings and data – updating in the field pharmaceutical industry ILiM – GS1 Polska addresses appropriate letters to all companies having databases of these assigned products with GTIN identifier with the prefix 590 belonging to the Polish National Organization GS1. Letters are addressed to the companies which are not registered in order to clarify these discrepancies. The company, whose products are coded GS1, including bar code EAN – 13, reflecting the GTIN identifier with the prefix 590, must be an active participant of this system. However, it is a foreign firm, which has received IDs from a pool provided by ILiM Ministry of Health (since 1999 only on the medication recorded), you must submit every year the relevant documents confirming the participation in the GS1 system in their own country or to sign up by the national representative of this company in ILiM - GS1 Poland. Active participation in the GS1 system should accour in the first quarter of this year, from which the first product was given the GTIN with prefix 590. We all are aware of the imperfections of the registration procedures and the provisions included in the trade legislation. It should be taken into consideration, however, that according to the content of the agreements occluded in 1999 and 2004 between the Ministry of Health and ILiM – acting as a National Organisation in Poland managing the global standards in economy, both the Ministry of Health and the Office of Registrations of Medicinal Products, Medical Devices and Biocides Products are required to pass on “for the particular firm information, which medicinal product has been assigned the number GTIN regarding the conditions of participating in GS1 system (formerly EAN. UCC). According to § of the above mentioned agreement “Giving an identification number of authorized medicinal product doesn’t entitle the company to using this number and presenting in the EAN.UCC barcode. User the number giving by GTIN requires the active participation of the economic unit in the EAN.UCC system.” Ministry of Health has been informed about sending to those companies that are not yet participants GS1 system calls for discontinuing doing those violations. In view of the facts that ILiM has also awareness that employers of the government institutions do not always perform their duties in a proper way in this range, do not charge any interest or other additional fees for over dating annual contributions. Such contributions always depend on the size f the company’s revenue obtained from the preceding year. Moreover in principle year contributions are unchanged for twenty years. At present works on improvement of the above mentioned agreement are continuing in order to rationalize the flow of information above the disposer’s duties having GTIN identifiers with prefix number 590. We hope that in future relevant informing producers and that economic-unit responsible and the companies representing foreign producers, which are issued certificates of registration witch the GTIN – 13 numbers, about the right to using them only by active participants GS1 systems, enable – to avoid misunderstandings.
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63
64 | logistics GTIN identifiers instead of the private identifiers type: BLOZ, BAZYL etc. For its part ILiM makes a lot of effort to raise the effectiveness
of medicinal products according to the global standards which brings significant benefits to the economy of drugs and medical goods and raises patient’s safety.
of drugs turnover in the entire supply chain. Among other things, in response to: •• Market demand - the manufacturers and distributors of pharmaceutical products (including medicines and medical devices, especially refundable)
20 years of barcodes in Poland and in the National Pharmacy GS1 system has been functioning in the world for 40 years of the twentieth century but Poland was incorporated into the system – as
•• The expectation of the National Health Fund
one of the last European countries barely in March 1990. As it ap-
•• The need of implementation of the project MZ health and e
pears from the listed dates, last year marked the 20 th anniversary of
Prescription
the Polish accession to the GS1 (first name: EAN system and then: EAN.UCC). Thus it was the 20 th anniversary of the accession of the
ILiM works for the operation of the central – national base above
Institute of Logistics and Warehousing (ILiM) the global organisation
mentioned products with a global identifier GTIN. The database will
of GS1. Exactly ILiM performs function of the national organisation
enable automatic and electronic data interchange according to the
GS1 from the very beginning and represent all the companies and
global standards ADC and EDI in the supply chain. We have already
organizations operating on Polish territory in the global system,
written about the base in the previous article from this series but we will
including global standards for the wide e-economy. In March 1990
return to the subject many times because this database is constantly
the first national companies in the pharmaceutical industry were
being improved in accordance witch the needs of its future users
registered in the GS1 system. This is also the 20 th anniversary of the
reported the market.
implementation of standards of marking goods and services, and
Because of that the active participants GS1 system can also update the current date for these products in a central website of the National
especially – packaging barcode on the Polish market. During 20 years the number of members, participants of the
Health Products Database – KBPOZ, created by ILiM visualization data
system gradually has increased. At present in GS1 Poland over
in collaboration with IMS Poland – the owner of FBD BAZYL and on the
18 000 companies are registered, including the increasing number of
basis of its data. KBPOZ functions, among other things, to enable the
producers in the health – care industry. All over the world there are
transition from the personal identifiers such as: BLOZ, BAZYL to the
over 1, 3 million such companies, and over 8 billion transactions is
global – GTIN.
based on GS1 standards.
GTIN should ultimately be used in all databases of the computer-
The number of Polish firms members of GS1 system over 20 years.
-firms serving the health-market to enable these companies to take advantage from the implementation of the effective automated systems (ADC) and Electronic Data Interchange (EDI) in the whole industry and with all companies and institutions both in Poland and abroad. In view of the fact that only active participants GS1 system in Poland are allowed to have “one stop shop” online registry of its products or
Novelties that are awaiting us are the theme of the Polish Council Conference of the GS1 system.
products of foreign manufactures, we also encourage to the active participation of companies that are only intermediaries in the Polish registration or introduce these products in the market. Therefore participation in the GS1 system is profitable for companies not obligated,
News that await us the theme of the Polish Council meeting of the GS1 System The main celebrations of the 20th anniversary of the GS1 Poland
including companies representing foreign producers who regularly
have been associated with the Congress Logistics & Eurolog, which ho-
confirm in ILiM their participation in the GS1 system in their own country.
sted the world’s most important representatives of logistics – with more
So we invite you to register in all firms being in the GS1 system.
than 750 participants from around the world. On the eve of the Congress
The aim of this system is to improve communication between economics-unit participating in the process of automatic identification
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- on 11 May 2010, at the Institute of Logistics and Warehousing was held a formal meeting of the Polish Council of the GS1 System, a
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logistics | 65 debate was opened by Janusz Targosz - Chairman of the Polish Council of the GS1 System in the current term. He presented the objectives and orientations. Indeed, the Council representing the interests of all participants in the GS1, including a large group of pharmaceutical manufacturers, indicates the main topics and issues which are handled in the GS1 Poland. The aim of the GS Poland is to work on improving supply chains. ILiM Director – Grzegorz Szyszka presented the multidirectional activities of the Institute of Logistics and Warehousing, which serves from the beginning the function of the Polish organization of GS1.The Institute is doing it perfectly, with a great commitment, is distinguished by a number of initiatives, also at the international level, which was especially emphasized in the speech presented by Miguel Lopera - President GS1 - global standards organization that manages the e-economy, who was the honorary guest of this meeting. The President of GS1 presented a vision of GS1 in 2020, and although in such a dynamically changing environment is not easy
Members of the chapter - from left: President GS1 - Miguel Lopera, Chief CGS1 - Dr. Elizabeth Hałas, Rector of the Higher School of Logistics - prof. Andrzej Korzeniowski, Director ILiM, President GS1 Poland - Grzegorz Szyszka and Vice-Director ILiM - Dr. Stanislaw Krzyżaniak, congratulate honoured persons.
to predict anything in 10 years forward, the fact that the director
Warehousing, which is an illustrative presentation of the functioning
of such a great institution - in fact brings together 150 countries -
of the magazine which uses automatic identification systems through
consider the future with such a long time horizon guarantees the
barcodes or radio-tags. In order to rationalize the management of such
usefulness of this system. During the deliberations of the Polish
stocks. Anyone who is not yet convinced of the purposefulness imple-
Council of the GS1 system also discussed the proposed topics
menting such a system in his company leaves the laboraty convinced of
before, including on:
the effectives of such solutions.
•• Future of barcodes in the context of the rapid development of new
The day ended with a gala dinner in the restaurant Brovaria, adding
technologies (we are still working on implementation the new bar
splendour to celebrating the 20th anniversary of GS1 in Poland, during
code symbolism – soon we will be writing about them)
which the most involved persons in the development and implemen-
•• The development of implementations and applications based on
tation of GS1 standards and solutions that improve the functioning of
EPC global standards that is barriers, challenges and opportunities
companies in supply chains and within their own companies through the
in the near future for implementing radio-tags on our product
use of e – economy were honoured. 20th anniversary of the implementation of barcode and GS1 global
packaging. •• The role of the GS1 Mobile Commerce (we are going to write on this
standards in the Polish pharmaceutical industry is also a time for
subject quite often because it extremely interesting and innovative
summing up. Initially, coding was only interested in domestic compa-
way to obtain information concerning goods from the pack by mobile
nies, exporting their products to the developed countries. This stemmed from the fact that for the vast majority of consumer
phone). •• New structure of GS1 – it should be more suitable for the needs
goods the necessary condition for accepting them by the foreign
of users – in this matter we also count on our Readers opinions,
contractor was having GS1 codes. Since 1992 also in Poland more
because GS1 is supposed to meet currently the needs of the market.
and more retail shops and warehouses have based the organization
•• Database of products as the global registry GTIN’s witch current and
of sales on automatic-identification-systems – ADC using barcodes.
reliable data and easy access and how this can be ensured by GS1. Miguel Lopera, Prezydent GS1
Currently, the propagation of ADC and barcodes also determines the fact that they are a part of increasing effects of the use of the Electronic Data Interchange which is also slowly entering our reality, although, for the time being, at first it concerns supply-chains. Probably many things will be changed when the national registers of products and companies with the global GS1 identifiers are set up and appropriate industry regulations are adjusted, which projects are being created now. All is done that companies could immediately implement solutions as a target. However, other companies which are still using internal, local, industrial and private solutions could move from these solutions to standard solutions, and thus much more profitable. Next, practical information, including how to create code markings
Participants in the meeting of the Polish Council of GS1 system had a chance to visit the laboratory of RFID Institute of Logistics and
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in the pharmaceutical industry and use them – we invite you tour new editions.
1/2011
66 | logistics
Recipe for logistics Joanna Dziedzic Consafe Logistics
The pharmaceutical industry imposes extremely high and complex demands on the drug supply chain. Providing a suitable temperature, humidity and absolute compliance with the deadlines for delivery of products are just some of the requirements which the logistics department of a pharmaceutical company must cope with. The key to its reliable operation is constant adaptation of the IT system to the current needs of the company, which seems easier today thanks to – inter alia – the use of advanced mobile solutions.
Their implementation optimizes all processes related to the management of the transport of drugs and provides complete control over
Mobile transport protection It is well known that drugs transported in poor conditions may pose
it – starting with order processing, up to the receipt of products by the
a threat to health and lives of patients, and therefore the pharmaceutical
appropriate drug store. What else does the pharmaceutical industry
companies are expected to obey the restrictive HACCP procedures
gain and why cannot it do without modern IT solutions?
(Hazard Analysis and Critical Control Points). A mobile system ensuring
The increasing competition in the market, as well as the binding
the appropriate transport conditions is an ideal solution for each
safety standards (GMP) make the drug producers develop the IT
company. Such a pharmacy-dedicated solution enables e.g. a constant
infrastructure, including the mobile solutions indispensible for the
monitoring of temperature inside vehicles transporting containers with
logistic industry. Mobile platforms make it possible to naturally
drugs. Any deviation from a given norm raises an alert at a terminal
embrace the critical business processes conducted outside of
or at the forwarder’s office. The impact of the system mobility on the
the company with IT support for data access and processing. In
increase in the shipment quality is visible also in case of crisis situation
case of pharmacy, the name “mobile solutions” refers to a set of
management. In the event of irregularities affecting the transported drug
intelligent tools, which automate a number of actions related to the
batches (e.g. a vehicle breakdown), the forwarder is immediately notified
distribution of drugs, which leads to minimizing the risk of delivering
of the situation. Forwarders can immediately contact the employees
the inappropriate consignments. The use of advanced technology
and therefore introduce quick remedy procedures, which may efficiently
brings also tangible financial benefits. It is much easier to decrease
prevent the delay in the product delivery. The solution supporting the
the costs of fuel consumption or shorten the route, if the forwarder
aforementioned processes is the ControlTransport designed by the
uses a transparent system indicating the current fleet status and the
Consafe Logistics company.
geographical location of each shipment. Here are some examples
Another example of improving efficiency by mobile systems is the
of how the mobile transport management system works in the
carrier circulation system.
pharmaceutical industry.
“The functional solution allows us to control and monitor the precise
1/2011
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number of containers in any given drug store,” – says Marcin Michalski,
ADVERTISIMENT
67
Consafe Logistics. “A driver is informed about the number of carriers that should be taken, and thanks to simple receipt functions the data is automatically introduced to the system,” he explains. The drivers may be monitored as well. Optionally, the system may be integrated with the Can-Bus used for data exchange, which allows fuel consumption, engine operating time or the number of kilometres monitoring. “It is a very good solution for the fleet managers who have a direct preview of what is happening to the given transport,” the fleet manager in a large shipping company sums up. The bar codes present on the containers are also a convenience, since they contain the encoded information about the name, series and the amount of the given drug. It is enough to scan the order to record the entire delivery in a system, thanks to which there is a certainty that the appropriate batch of drugs is delivered to the drug store.
Timely diagnosis The flexibility of operations is important for any logistics company. The ControlTransport systems makes it easier to optimize the drivers’ work due to the ongoing management of their work by the forwarders. The system makes it possible to update the data on mobile devices and the management part in the real time. The forwarder sees in the system the number of executed orders, their status and position, and may therefore react quickly and efficiently to the needs of a customer or to emergency situations. Thanks to this the organization becomes more agile, and the customer’s satisfaction increases. The mobile application monitors the shipment at each stage of its transportation, enhancing the flexibility of fleet management and increasing the number of deliveries to drug stores up to even a couple dozen per day. “With the help of integrated and fully mobile software, customers receive online information about the delivery status, which certainly enables them to provide reliable date to patients about the availability of drugs in the store,” explains a pharmaceutical company representative.
Where time matters most Not only does the solution simplify and automate numerous procedures related to the delivery of consignments, but it also decreases the amount of paperwork and administration. Another benefit related to the implementation of the advanced mobile solution is the option of printing and invoicing directly after the delivery of the product to the drugstore. The preparation of claims documentation is another example of how the work is sped up. It is enough for the driver to take photographs of the damaged goods, and then introduce the scan of the photograph to the mobile device, and the system will control all other activities. The new technologies make the organization meet its business objectives more quickly and efficiently, minimizing the related risk at the same time. For these reasons, investments in mobile solutions supporting the work of employees and assets in the field are becoming a standard. Better management and quicker response time have a direct impact on the results and the customer satisfaction.
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C + N Polska Sp. z o.o. ul. Wojska Polskiego 6, 39-300 Mielec, tel. +48 (17) 773 80 01, fax +48 (17) 773 80 09 / 14, cplusn@cnpolska.pl
68 | packages
Medicine packaging as industrial design and subject of copyright Monika Kowalczyk Patent spokesperson, Chałas i Wspólnicy Legal Office
There is no doubt that the appearance of packaging is of great importance to consumers, and this also applies to medical products. Good packaging increases the value of the whole product, so protecting it should be one of the priorities of marketing strategy. The packaging of medicine may be protected as industrial design, or it may be subject to copyright as a work.
Protection of packaging as industrial design or as a work is cumulative
unregistered design. Protection is territorial, and must be acquired
in nature. It should be remembered, though, that according to art. 116
nationally (in local patent offices), regionally (e.g. in the Office for
of the Industrial Copyright Act, “the protection of material rights to
Harmonisation in the Internal Market in Alicante in Spain, covering the
a work, as provided for by copyright legislation, does not apply to works
territory of the European Union) and internationally (according to the
created according to an industrial design and introduced into circulation
Hague Convention on international registration of industrial designs
after the expiry of the registration right granted to such a design”. After
administered by the World Intellectual Property Organisation). In Poland,
the protection period expires the work is in the public domain, meaning
protection is granted for a maximum of 25 years divided into five year
that from then on it can be used freely, i.e. without the necessity to
periods (the relevant fee is paid every 5 years).
seek permission or pay royalties. Cumulative protection thus only exists during the period when the exclusive right lasts, until the time it expires. Copyright protection ends after the protection period expires (in the
Protection arising from copyright Copyright protection of packaging is attractive as it lasts for 70 years
event that registration rights are waived) or when periodic payments
after the death of the creator. What is more, no formalities or fees are
are not made.
required to acquire protection. Not every design will meet the criteria of a work, though. The external form of a product may be protected as
Industrial design
a work of industrial design on condition that it constitutes an expression
Industrial design is a new form of a product or part of one, which
of creative activity of an individual character. For packaging to qualify as
has an individual character and is made specific by its lines, contours,
a work, it must have all of the following features – be the result of human
shape, colour scheme, texture or material, and by its ornamentation.
effort, an expression of creativity and have an individual character. Even
Protection may thus cover, for example, a product’s packaging or
once the rights from registering the industrial design have expired, the
the graphics on it, as well as the labels or leaflets attached to the
personal copyright of the creator remains protected, which is the right
product, or the typeface (of letters or digits). Industrial design is granted
to author the work, to mark it with one’s own name or pseudonym, or
a registration right, but under EU law may also be protected as an
to provide it anonymously, the right of the integrity of the work, right to
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69
supervise the way in which it is used, etc. These rights are not limited in
occurs when products containing a given design were introduced into
time and cannot be waived.
circulation, displayed at trade fairs or exhibitions, or in relation to this, published in
Prerequisites for protection of medicine packaging as industrial design What should encourage creators to protect packaging by registration? It may be said that the registration system is beneficial both for
a company’s catalogue before the application was submitted.
Right to an unregistered EU design The right to an unregistered EU design arises in the same way
creators and their competitors, as there is then no doubt as to who
as copyright protection, namely without the requirement to fulfil any
acquired the rights to a given design, when, and which of its features are
formalities. It is limited in time and lasts for 3 years from the appearance
protected. The competition cannot make the excuse of not knowing that
of the design in the European Union. Protection of an unregistered
a given design existed, but on the other hand will not incur costs
design gives businesses the chance to check the demand for the
of producing packaging which violates the exclusive rights of third
given products before registering the design. This allows them to avoid
parties. Not only may the person entitled to an industrial design produce
investing in protection of the design of a product which failed on the
it himself, but also earn money by licensing it. The doctrine also indica-
market. It should be remembered that the creator has twelve months
tes that the criterion of novelty applied when assessing the possibility
from the design becoming publicly available to apply to register it.
of registering a design is far more precise than the criterion of originality applied for copyrights. A work is still original even when an identical work exists. The only condition is the circumstance that
Protection may accumulate Regardless of the ways indicated above to protect packaging for
the author created the work independently of the existing work.
medicine it should be remembered that this may also be protected as
Industrial property law works differently, though. The later work may be
a trade mark, utility model, invention or on the basis of the Act regarding
original in the understanding of copyright law, but may not be subject to
prevention of unfair competition.
the protection resulting from industrial property law since there exists an identical or very similar design. It is irrelevant that the designer did not know of that design’s existence. On the other hand it should be remembered that although proof of registration constitutes a presumption of the design’s validity, this registration does not however guarantee protection, as it may be undermined – the right from registration may be annulled. As far as registration costs are concerned, they are not so high compared with the costs which would be incurred if a dispute were taken to court. It should be remembered that one application may cover separate forms of a product with significant joint features (variations of the industrial design). It is also significant that under copyright law protection is only acquired against plagiarism (copying), and under industrial property law there is the right of exclusivity, which entitles the holder to stop non-deliberate violations. In many cases long-term protection of a design is not necessary, as the fashion for certain designs often passes quickly. In the doctrine the point is even raised that the copyright protection system, with its long-term protection which once seemed so attractive, is becoming inadequate with regard to industrial design, due to the fast-paced development of technology and appearance of ever newer forms of production. The 25-year design protection period stipulated in the registration system is entirely sufficient to regain the investments spent by the right holder. Bearing in mind the novelty criterion (on a world scale), a product cannot be tested on the market before the application to register it. Exceptions to this rule are the so-called period of grace, and the possibility already mentioned to acquire protection of an unregistered EU design. In many countries, including Poland, it is possible to register a design even if it has been publicly available for the period of six or twelve months preceding the application. This
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70 | packages
Certified safety guarantee Urszula Bandoch, Beata Kornowska Cezar S.A. A Chesapeake Company
Have you ever wondered when buying medicine if it is what it says on the packet? As patients, we place immense trust in pharmaceutical companies by putting our health in their hands. Manufacturers of packaging for the pharmaceutical industry are also aware that customers must feel safe, that they must be given a safe product.
As packaging producers for the pharmaceutical industry we realise
to the goods. Another equally vital function for this industry is to inform –
that one mistake by us can cost someone their health or even life, and
the buyer learns the type and properties of the product, production date,
our professional ethics oblige us to get our job done right the first time.
method of use, use-by date, price and manufacturer.
We build our reputation, which is our most lasting capital, because we bear the enormous responsibility which is human life. It is therefore fundamental that we introduce and closely follow procedures, strategies, good manufacturing practices and also apply methods and tools to eliminate even the slightest risk of error. The basic requirements accepted by pharmaceutical companies and
Risk Management in the Process of Manufacturing Packaging for the Pharmaceutical Industry A team is appointed to develop and implement pharmaceutical standards, consisting of people with the relevant knowledge regarding the products, processes and dangers characteristic for pharmaceutical
set for packaging suppliers are set out in standards ISO 9001:2008, ISO
packaging. The risk management process is carried out according
15 378:2006 and PS 9000. Without these we as a company would not
to a defined plan. The EN ISO 14971 standard (Medical devices –
be able to produce pharmaceutical components or packaging. We must
Application of risk management to medical devices) is very helpful
be sure that all the requirements of the above standards are consistently
in this regard. There are various risk analysis techniques, e.g. PHA,
met and we must aim to obtain accreditation.
FTA, FMEA, HAZOP and HACCP, of which the most popular in the
On the subject of packaging safety, we should concentrate our
pharmaceutical industry is FMEA ( Failure Mode Effects Analysis).
attention on the functions of packaging for pharmacy, where the most
Using this method, the risk of each identified threat is calculated and the
important is undoubtedly its protective function, intended to protect the
actions minimising the risk using existing methods of control are defined
product against the effects of external factors. The practical value must
for each stage of the packaging production process. When calculating
be safeguarded by the packaging to ensure freshness, durability and an
risk, other criteria for estimation are also taken into consideration, such
attractive, aesthetic appearance. The packaging should prevent decay,
as severity, probability of occurrence and detectability. Acceptable risk
colour changes, changes in consistency, evaporation, dirt and damage
levels and critical points are defined based on the stipulated principle. Critical dangers in pharmaceutical packaging are: •• contamination by another product, designs being mixed up; •• missing text; •• the quality of the statutorily required information printed in Braille. Each newly identified danger from various sources, such as information from the market, customers’, patients’ and users’ complaints and comments, data from the literature, medical incidents, etc., is taken into account when verifying the risk analysis.
Validation Policy In order to obtain safe pharmaceutical packaging of a defined quality in line with customer expectations, all critical processes, equipment
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71 and auxiliary installations must be subjected to a qualification/validation process by:
Staff and Visitor Hygiene There are also restrictive standards covering staff who have contact
•• Conducting retrospective qualification/validation in the event that a
with the production, and these mainly concern clothing – the use of
process is already under way and the product is being distributed;
protective clothing, hair protected with a head covering, disinfection
•• Conducting prospective qualification/validation for all implemented
of hands (which must always be done when entering the production
critical processes, new equipment and installations •• Conducting periodic re-qualification of equipment and installations, and revalidating processes in the event that no changes have taken place.
area) and a ban on food consumption. Personal belongings may not be brought into the production area, and wearing jewellery is prohibited. Visitors to the production area move around keeping to marked paths and are required to wear protective clothing. These are a few examples
Risk analysis by a method such as FMEA ( Failure Mode Effects Analysis) is used to define the scope of qualification and validation work.
of actions preventing the risk of contamination of the product. Standards PS 9000 and ISO 15378 define the standards of hygiene applied in the manufacture of packaging for pharmaceuticals. In case of doubt,
Environmental Conditions Packaging materials intended for contact with medicinal products are manufactured under defined environmental conditions in accor-
use the FMEA method and assess the degree of identified risk for the pharmaceutical product and then implement the appropriate preventive action proportionate to the estimated risk.
dance with the requirements of standards PS 9000 and ISO 15378. If required, clean rooms or zones are classified according to the ISO 14 644 family of standards.
Controlling Cross Contamination In order to eliminate contamination of a product, during the entire production process products are segregated and identified. The production lines and work areas manufacturing pharmaceutical packaging should be divided, and permanent partitions installed where necessary. Before commencing each batch of production a documented control of the production line is carried out, to check that it has been cleared of previous materials, products, waste and documents. After each batch is completed a documented cleaning of the line is carried out.
Quality Control During the production process, employees at a given work station measure those parameters which have the greatest influence on product quality, and whether the customer’s requirements are being met. This makes it possible to ensure that a given product meets the set parameters at every stage of the production process. Any critical deviations in quality are investigated, explained and documented. Pharmaceutical products are released for dispatch by the Quality Control Department after the necessary procedures and measurements, including checking that the records for a given batch are complete. To verify the constant functionality of the automatic checking equipment, regular documented sample tests are conducted. These checks are done before a batch is started and at regular intervals during production of a batch or order. One of the devices subjected to this type of verification is the flap code reader installed in the machine for folding and taping boxes. The intention of certified suppliers of packaging for the pharmaceutical industry is to ensure first of all safe products and high service quality as part of the Good Manufacturing Practices ( GMP ). Quality control, which is part of GMP, aims to ensure that a product released into circulation meets all the standards set. All the strictly defined procedures serve one purpose – to protect human life and health. The article describes only certain elements of the certified system for producing packaging for the pharmaceutical industry which are considered the most vital from the point of view of product safety.
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72 | reports, projects, plans
Generic drug market in Central Europe will grow by 6% per annum between 2011 and 2013 Agnieszka Stawarska Pharmaceutical market analyst PMR Publications
In 2010 the generic drug market in Central Europe increased by 12%, whereas that of original medicines grew at a rate of around 10% in euro terms, according to information contained in the latest report by PMR, a research and consulting company, entitled “Generic and innovative drug market in Central Europe 2011”. In 2011 and 2012 the trends which boosted generic sales in 2010, including price pressure and other restrictive measures, will continue. This is why the generic market will develop more rapidly than its original counterpart during these years. According to PMR estimates, the generic drug market will, therefore, develop at a CAGR in excess of 6% between 2011 and 2013, whereas original drugs will grow at a rate of 4% during the period in question. Price cuts aimed at healthcare budget savings In 2009 and 2010 several actions were taken by Central European
for drugs with the same active ingredient, adjusted to the price of the cheapest alternative.
governments with the aim of saving money in the healthcare arena. For example, in Bulgaria a multilateral agreement was signed betwe-
Poland: will legal regulations hamper innovation?
en the Bulgarian National Health Insurance Fund (NHIF), pharmaceutical
As clinical trials are one of the main modes of access to the most
manufacturers and wholesalers, and organisations representing doctors
innovative medicines for Polish patients, it is quite easy to recruit clinical
and patients, during a meeting held on 30 April 2010. The innovative
trial participants in Poland, in comparison with other countries. The
pharmaceutical manufacturers (24 companies belonging to the
potential of clinical trials in Poland is, however, not used to the full, as
Association of Research-Based Pharmaceutical Manufacturers) agreed
a similar number of trials (450-500 per annum) are carried out in, for exam-
to offer a 5% discount on all drugs for which the NHIF pays between
ple, Hungary and the Czech Republic, countries with smaller populations.
June and December 2010. If all pharmaceutical manufacturers adhered
One of the reasons for this is the ambiguous legislation, which, according
to this agreement, this would save the NHIF approximately BGN 1.5m
to the results of a survey carried out by PMR specifically for the purposes
(€0.7m) per month.
of the “Clinical trials in Poland 2010” report is the second most obstructive
In October 2010 the Slovak Health Ministry re-introduced the degressive margin on medical supplies to hospitals. The ministry believes that this is an effective instrument for the regulation of drug consumption
obstacle to the development of companies operating on the Polish clinical trials market: this was indicated by 37% of respondents. There is no single legal act in force in Poland, which would regulate
in Slovakia and for reductions in the costs associated with drug policy.
the clinical research market comprehensively. The relevant provisions
It expects cost savings of approximately €10m per annum.
pertaining to the clinical trials market are contained in various legal acts
In the Czech Republic in 2009 the State Institute for Drug Control
of various categories, including those relating solely to the pharma-
(SUKL) concentrated on changes to ex-factory prices for reimbursement
ceutical market (e.g. the Pharmaceutical Law), but also the Civil Code
medicines, which were started ex officio in 2008. In 2009, maximum
and the Penal Code. It is also worthy of note that provisions of various
prices were reduced for 390 SUKL codes (by 29% on average), and
acts are frequently inconsistent with each other. In December 2009 the
increased for 190 SUKL codes (by 84% on average). The SUKL
Ministry of Health published the assumptions underlying the Clinical
expected to save CZK 2.4bn (€94.9m) by means of the revision of the
Trials Act, but the act still has not come into force.
prices of 1,270 reimbursed drugs introduced on 1 April 2010. As a result of this, health insurance companies would pay the same amount
1/2011
Another problem is VAT applied on clinical trials. In these area Poland has still not harmonised its legislation with the European Union
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73 directives. Pursuant to the so-called VI EU Directive, expert services, including clinical research, should be subject to taxation only in the country of the client; nevertheless, most companies operating in Poland
Slovakia: reimbursement reform to boost generic consumption After an allegation that the Categorisation Committee lacked
pay 22% VAT (23% VAT rate from 2011) as the monitoring of clinical
transparency, the Slovak Health Ministry has decided to make drug policy
trials, according to the effective statistical classification can be classified
more open and the individual steps within the categorisation process of
into four different groups of services and which group it is categorised
drug reimbursement more transparent. Several regulations pertaining to
under depends on the civil servant’s interpretation.
the drug reimbursement system could come into force in Slovakia in 2011.
A client from an EU member state or Switzerland commissioning the
The proposed changes in the area of generic and innovative medi-
organisation of a clinical trial in Poland can request to be reimbursed the
cines include the earlier appearance of generics and conditional drug
tax; however, the reimbursement is very time-consuming. The situation
categorisation, along with the introduction of API prescription by doctors.
is even more difficult in the case of firms headquartered in the United
The proposed changes will allow the submission of applications for
States where there is no such thing as VAT. For them the 22% VAT
the categorisation of new drugs before a decision on their registration
comprises an additional cost. Thus, these firms most often decide to
has been made. As a result, the assessment of applications for
conduct clinical trials in countries other than Poland.
registration and categorisation will be carried out simultaneously. The
Improvement in these areas would not only lead to an increase in the number of clinical trials conducted by international concerns in Poland (which would improve patient access to innovations) but could also en-
ministry believes that this move will accelerate the arrival of cheaper generics on the market and save about €5m per annum. The Health Ministry is also considering the introduction of new
courage domestic manufacturers to invest in innovative medicines. This
regulations which will stipulate that doctors in Slovakia should prescribe
could, in the longer term, prompt an increase in the share of innovative
only the active pharmaceutical ingredient (API) instead of the specific
medicines as a proportion of the Polish pharmaceutical market, which is
drug name. A pharmacist would then advise patients on the drugs
one of the leas substantial in Central Europe.
available, particularly those which carry the lowest co-payments, and patients would take the final decision. The new system would not cover
Hungary: R&D expenditures no longer tax-deductable A Hungarian government proposal suggests that drug manufacturers in Hungary will no longer be able to deduct their R&D expenses from the fee of the medical sales representative and the 12% tax on revenues from reimbursed drugs paid to the National Health Insurance Fund (OEP). The legislative changes could constitute a burden for some of the largest drug manufacturers on the Hungarian pharmaceutical market. These include Egis and Gedeon Richter, which paid HUF 1.8bn (€648.1m) and HUF 2.1bn (€756.1m) respectively to the OEP in 2009. This could also adversely affect manufacturers of innovative drugs, which may, as a result, reduce their R&D spending. The deduction was introduced in 2009, when 20% of the R&D costs could have been subtracted from the expenditures, and this was increased to 100% in 2010. The Hungarian government is also planning to change the existing system which involves obligatory courses for doctors who allegedly prescribe excessively expensive medicines. It hopes, instead, to convince doctors to prescribe cheaper generic drugs, thus saving public money by establishing an incentive system. It is estimated that HUF 3-4bn (€11-14m) could be saved every year if the doctors used the system. Furthermore, pharmacists would also be involved and rewarded when they replace a prescribed medicine with the product with the lowest reimbursement level. More information on the generic and innovative drug market in Central Europe, along with the reimbursement policies of individual countries, can be found in the PMR report entitled “Generic and innovative drug market in Central Europe 2011. Comparative analysis, reimbursement policies and development forecasts for 2011-2013”.
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all drugs – cancer and psychiatric medication would still be a matter for the doctor. At the moment, the schedule for the introduction of the new prescription system is not clear. ADVERTISEMENT