Świat Przemysłu Farmaceutycznego 1/2012 EN

NR 01/2012 (19) 10 PLN (INCL. TAX 5% VAT)

The Farmacom publishing house, the editorial office of the “World of the Pharmaceutical Industry” quarterly cordially invite you to take part in 4 THE WORLD OF THE PHARMACEUTICAL INDUSTRY CONGRESS 2012

4 Congress th

World of the Pharmaceutical Industry epresentatives of pharmaceutical manufactures and companies are invited to participate with specialists of the industry in this meeting Representatives 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 packaging of ready products.

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

List of advertisers: Quarterly, published by FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 farmacom@farmacom.com.pl www.farmacom.com.pl Editor-in-chief Robert Miller tel./fax +48 32 455 31 61 tel. kom. +48 502 084 101 robert.miller@farmacom.com.pl Subscription and distribution FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 tel./fax +48 32 455 31 61 prenumerata@farmacom.com.pl

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The magazine is addressed to process and production engineers, automatic systems specialists, heads of production, control and quality assurance divisions, heads of logistics and procurement divisions and product development divisions at pharmaceutical companies. The magazine is also purchased by organizers of trade fairs, conferences and industry training courses, government offices, ministries, institutes, higher educational institutions offering pharmaceuticals-related courses, and design firms. The editors reserve the right to shorten and edit material.

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contents

11

Managenent of waste electrical and electronic equipment in the pharmaceutical industry

19

When

PAT stimulates innovation

6

Investment in innovative solutions

19

When PAT stimulates innovation

8

The use of Raman spectroscopy to identify raw

22

Preparing a coating mixture with Eudragit E PO

materials and pharmacologically active substances 11

Managenent of waste electrical and electronic

– technological problems and suggested solutions 24

equipment in the pharmaceutical industry 13 16

Quality vs. Optimisation

Emulsifying in a batch process 26

How to optimize efficiently?

New process optimization method

The changes in interpretation of the scope of the supplementary protection certificate (SPC)

Realize the problem, solve the problem.

30

Impurities in generic drug substances and products

for medical products

1/2012

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The changes in interpretation of the scope of the supplementary protection certifi cate (SPC) for medical products

35

34

Trigger

happy

16

Quality Packaging Solutions

8 The use of Raman spectroscopy to identify raw materials and pharmacologically active substances

44

Modern warehouse in the pharmaceutical industry

for the pharmaceutical industry 35

Trigger happy

38

In-Mould Labelling

40

Kujawskie Zakłady Poligraficzne Druk-Pak S.A. – leader in the production of pharmaceutical packaging in Poland

42

Process Train Containment in CMO Operations

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46

Polish dietary supplements market to reach PLN 2.5bn by 2012

1/2012

66 | Polish Polishindustry industry

Investment in innovative solutions Robert Miller, the editor-in-chief of FARMACOM Publishing House, talks to Maciej Adamkiewicz, Adamed CEO.

What challenges is the pharmaceutical industry in Poland and abroad facing in the nearest future?

A real challenge for the Polish companies is investment in innovative solutions as only they can guarantee the companies’ competitiveness on global markets. It is utmost important for the whole sector to arrive at a common strategy for the medical and pharmaceutical sector: in the short-term for generic medicines, in the mid-term for biosimilar medicines and in the long-term for innovative medicines. We have to work on them concurrently as realizing the innovation-related strategy won’t be possible without the first two ones.

How do you assess the level of innovativeness of the Polish pharmaceutical industry and the scale of outlays on innovative solutions?

Polish companies, including also the Adamed Group, understand it perfectly well and are conducting works on innovative projects. The most important stage is making a decision that we want to go in the direction of innovative solutions. We have made such a decision and consequently, we have been acting accordingly for 25 years. Together with our partners, about 200 people work on innovative projects in the Adamed Group. It is necessary to arrive at a common strategy for the whole sector, which will

I mean large specialist national and foreign entities which have adequate

define the public-private partnership but which may also facilitate acquiring

resources and experience, middle sized entities with a potential for

external funds. Moreover, one should think about what consequences for

development and also universities and other R&D facilities with their

the companies’ own outlays on R&D will be brought by the mechanisms

respective technical equipment and scientific employees. And eventually

specified in the reimbursement act, which is to enter into force from 1st

the support of a government as a partner is needed. The involvement

January 2012.

of each of the above mentioned entities plays an important role for the development strategy of the Polish pharmaceutical sector. The EU funds

Is the innovative approach of the Polish pharmaceutical plants somehow supported (for instance by the government or institutions)?

What kind of support or help do you expect?

constitute an important source of support for the whole sector. I evaluate the average subsidies for projects submitted by the pharmaceutical industry at approximately 30 per cent. For small and big companies they may respectively amount to 50 and 80 of the project value whereas the

To develop innovative products the main interested parties present

companies have to finance the rest with their own funds. On the other hand,

on the pharmaceutical market have to cooperate with one another:

projects submitted by universities may be granted even 100% financing.

1/2012

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ADVERTISEMENT

How do you evaluate the cooperation between the „pharmaceutical industry” and „science” in Poland?

With all certainty there is still a lot to do in this area but I personally have a positive opinion about the cooperation. I appreciate that the scientific circles are open for discussion. Dialogue has enabled us many times to diagnose problems which are important from the point of view of the entire sector, which made it easier to find a common solution for them. In the Adamed Group, we cooperate both with universities and with small biotechnological companies. Our biggest assets are people whose

Widest range of reference materials and proficiency testing schemes

knowledge and experience allows us to strengthen the position of our company every day– on the Polish market and globally.

Do different clasters and associations help increase the innovativeness in the pharmaceutical industry?

I think that their role is not fully appreciated in Poland yet. Taking into consideration their specific operations, clasters and associations should be involved in preparing five- and ten-year strategies for the sector. One should think carefully how they could be included in the whole sector’s operations. Their organizational and operational variety will allow to arrive at better solutions. Cooperation with such companies and institutions is popular worldwide and brings mutual benefits for both partners.

What can Adamed be proud of about in terms of innovativeness?

What are you working on now?

● pharmaceutical reference substances and impurities with certificate of analysis ● European, British, US Pharmacopoeia reference substances ● Pharmacopoeia publications ● phytochemical reference standards ● physical property standards (like conductivity, refractive index and viscosity standards) ● ATCC Reference strains and cell lines ● many others …

To start work on a new medicine, one has to first diagnose the patient’s need, properly define it and find the right and effective solution. Currently, we are conducting works in the area of neuropsychiatry, oncology and metabolic diseases and the last area is the biggest challenge as metabolism has influence upon development of tumors and central nervous system disorders.

We are working on solutions which are to treat schizophrenia, bipolar disorder,

LGC Standards also offers a possibility to prepare standards meeting specific customer’s needs on request.

depression or Alzheimer disease in terms of metabolism. When it comes to metabolism we have already reached the stage of clinical trials.

Adamed celebrated its 25th anniversary this year. What are the president’s plans or wishes for the next years? How do you imagine the company over the next few years?

Should you wish to obtain more information, please visit our website www.lgcstandards.com or contact local LGC Standards office:

First of all, I assume systematic development of the innovative projects we are conducting. I do believe that we have an opportunity to expand beyond generic medicines in terms of revenues and we will be focusing our operations on this goal. The Adamed Group also has ambitions to become a global company. Our goal in the future is to introduce more new products from the company’s portfolio onto international markets. We hope that proceeds from sales will be generated to an ever larger extent by international markets.

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LGC Standards Sp. z o.o.

M. Konopnickiej 1 Dziekanow Lesny 05-092 Lomianki, POLAND tel. +48 22 751 31 40, +48 22 751 55 69 fax +48 22 751 58 45 e-mail: pl@lgcstandards.com

8 | Polish industry

The use of Raman spectroscopy to identify raw materials and pharmacologically active substances Aleksander Ciesielski Łukasz Uścinowicz Quality Control Department, Polpharma PLC

The ever increasing quality requirements for pharmaceutical manufacturing dictated by legislative regulations cause the need to introduce an effective and efficient system for verifying the identity of raw materials in each package. Therefore, it is not enough that before starting the production a manufacturer will examine the sample representative of the whole batch, but it is required to test all containers of a certain batch for their identity. This is not a major problem when the plant consumes daily a dozen or so packages of starting materials. The problem appears in case of high production volume, which requires the use of even hundreds of containers of different starting materials a day.

The comparison of available analytical techniques

spectroscopy in a range of near-infrared (NIR). When a user is determined to quickly realize the project entitled „The conformation of the identity

Manufacturers who produce the measuring equipment meet the needs

of raw materials in each package” with minimal effort devoted to the

of pharmaceutical industry by building more and more precise devices

development of analytical methods, the use of Raman spectroscopy

that allow faster response in the form of an accessible report with great

should be considered.

certainty of the outcome. Spectroscopic techniques absolutely lead the way in confirming the identity of pharmaceutical raw materials. IR, NIR and Raman spectroscopy are most commonly used to confirm the identity. Table

Raman spectroscopy – history and measuring principle

1 shows basic properties of the above-mentioned spectroscopic techniques.

Raman spectroscopy was started by Smekal’s discovery in 1923,

Raman spectroscopy has only recently been fully appreciated,

which was based on observing the characteristics of scattered radiation

especially as a complement to the analysis performed using the method of

and mainly the fact that apart from the photons with frequencies of

FT-IR

Raman

NIR

Selectivity

High; specific spectrum-the possibility of direct interpretation

High; specific spectrum-the possibility of direct interpretation

Low, the need to use chemometric methods

Confounding factors

Presence of water in the sample

Contamination of the sample can cause fluorescence-signal disturbance or an increase in the time of spectrum acquisition

Presence of water in the sample; the shape of spectrum also results from physicochemical properties of the sample

Preparation of the sample

KBr tablets, milled pieces in paraffin oil, possible measurement without previous preparation of the sample by using the ATR attachment (Attenuated Total Reflection)

Possibility to scan the samples placed in glass or plastic vessels and the use of fiber optic probes

Possibility to scan the samples placed in glass or plastic vessels and the use of fiber optic probes

Mobility of the measurement system

Typical stationary devices

Stationary/portable

Stationary/portable

Labour intensity of creating methods

Low-most commonly visual evaluation and the assessment of similarity with the model spectrum

Low-just enter reference spectrum

High-based on a set of calibration spectra and chemometric methods

Tab. 1. The comparison of spectroscopic identification techniques

1/2012

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9 a)

0.444 0.42 0.40 0.38 0.36 0.34 0.32 0.30 0.28 A

0.26 0.24 0.22 0.20 0.18 0.16 0.14 0.12 0.10 0.076 12000.0

11500

11000

10500

10000

9500

9000

8500

8000 cm-1

7500

7000

6500

6000

5500

5000

4500

4000.0

0.740

b)

0.70 0.65 0.60 0.55 0.50 0.45 0.40 A 0.35 0.30 0.25 0.20 0.15 0.10

0.036 4000.0

c)

3800

3600

3400

3200

3000

2800

2600

2400 cm-1

2200

2000

1800

1600

1400

1200

1000

800

650.0

3.25 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 INT

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0

-0.25 3278.0 x1e4

3000

2800

2600

2400

2200

2000

1800 1600 Raman Shift / cm-1

1400

1200

1000

800

600

400

200.0

Fig. 1. Sample spectra: a) near-infrared (NIR), b) IR spectrum, c) Raman spectroscopy

incident radiation υo, the photons with frequencies υ ≠ υo appeared [1].

a measuring window of the apparatus (or probe) to the tested material and

Five years later, an Indian physicist Sir Chandrasekhara Venkata Raman

recording the spectrum directly from the pack.

experimentally confirmed the predictions of his predecessor by observing the phenomenon of scattering radiation in liquid (benzene). Hence in physics, the phenomenon of inelastic light scattering on elementary particles

The practical application of Raman spectroscopy

is known as Raman scattering. In 1930 Raman was awarded the Nobel

The need to confirm the identity of pharmaceutical raw materials from

Prize for his work on light scattering, while the discovered phenomenon

each package used in the production contributed to searching for innovative

was named after him.

solutions in the field of analytical techniques. This search resulted in the

Already in the thirties of the twentieth century, many aspects of Raman

application of Raman spectroscopy at the Quality Control Department of

scattering were described in theory, however, due to high complexity of the

the POLPHARMA PLC Pharmaceutical Plant in Starogard Gdański. This

measuring equipment, an interest in Raman spectroscopy was not large. It

technique is relatively insensitive to physical and environmental factors

was not until the end of the last century, when thanks to the development

such as particle size, moisture and issues connected with the packaging

of modern technologies, electronics, including the improvement of lasers

material. This insensitivity combined with high molecular selectivity allows

and miniaturization, the equipment used in Raman spectroscopy has been

highly flexible development of the method when using this technique. In

significantly simplified.

fact, this method can be generally based on a single reference spectrum.

The mechanism of Raman scattering is as follows: the incident

This allows extremely short time that is required to build the library and

electromagnetic radiation (photon) induces a dipole moment in the

rapid implementation of the analytical method which enables testing of

molecule which is dependent on the polarizability of the molecule. The

the actual samples of raw materials.

weaker the bonds between electrons of the outer layers and the nuclei

The effectiveness of the method is an important aspect to be taken

of atoms are, the higher polarizability is. When the molecule vibrates and

into account when assessing suitability of the analytical method used to

causes periodic alternations in its structure, also polarizability changes.

confirm the identity. In the context of testing the identity, specificity is a

The measurement of electromagnetic wave scattering can therefore be

parameter that must be demonstrated during validation of the method.

a source of information about electron interactions. Since the intensity of

When assessing the identity of the material on the basis of spectral data,

scattered radiation is several orders smaller than the intensity of exciting

the unknown spectrum is compared with one or more reference spectra.

radiation, it is necessary to use radiation sources with high power (lasers)

The final assessment can be done by visual comparing the similar position

and sensitive detectors [2].

of the main bands and their intensity, but usually the whole spectrum is

The great advantage of Raman spectroscopy is the ease of preparing

automatically compared using the appropriate mathematical algorithm.

the sample for analysis, for instance there is no time-consuming preparation

Therefore, the use of a particular algorithm plays a key role in the final

of KBr tablets. In modern apparatus the measurement is based on attaching

evaluation and has an impact on the level of specificity that can be achieved

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1/2012

10 | Polish industry using a given analytical technique. A commonly used mathematical approach to comparing spectra is based on searching in the library the spectrum which is characterized by the best correlation coefficient compared with the unknown spectrum.

The study used a portable Raman spectrometer, equipped with a Triggered Fiber Optic Probe (TFOP). 46 substances used in pharmaceutical industry were tested to confirm the usefulness of the Raman technique; these were both active ingredients (APIs) and excipients. The creation of methods used to test production samples requires registration of a reference spectrum for the material whose identity was confi rmed using another validated analytical method.

This spectrum is later used to compare with the spectrum of an unknown substance and the final verification of sample identity. The reference spectra were recorded on the samples placed in polyethylene bags and were examined directly through packaging. Laser radiation of wavelength 785 nm was directed on the tested material using a measuring probe ended with a special aperture which allows appropriate beam focusing.

The library was built based on the collected reference spectra. The substances were classified into several groups in terms of spectra registration parameters, and thus separate test methods were created for each group. Validation of the developed methods was the next step to verify their suitability for routine confirmation of raw materials identity. This was done in the spectra library on three batches of each substance; the tested parameters included specificity and robustness.

Figure 2 presents the matrix of specificity for the tested substances.

It shows that a particular starting material is identified as one raw material (similarity coefficient higher than 0.98), which indicates specificity

20. citric acid x 1H2O

19. anhydrous citric acid

18. boric acid

17. aminoacetic acid

16. alginic acid

15. copovidone (Kolidon VA-64)

14. povidone (Kolidon K-25/K-30)

13. KlucelHXF

12. crystalline glucose

11. polyethylene glycol 6000

10. Eudragit RS-PO

9. Eudragit L100

8. Eudragit L100-55

6. sodium dihydrogen phosphate x 2H2O

7. ethylcellulose

5. sodium tetraborate

4. crystalline cellulose

3. microcrystalline cellulose

2. carbomer (Carbopol 94P)

1. butylhydroxyanisole

of the method.

Fig. 3. A portable Raman spectrometer for routine use

Summary

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Portable Raman spectrometers are in many ways an attractive alternative to conventional analytical methods. High specificity together with the ability to use mathematical algorithms significantly reduces the time and effort during developing the methods. This leads to achievement of a rapid and reliable analytical tool. A large number of samples that have to be tested can not disturb the continuity of manufacturing process and maintaining the compliance with regulatory requirements and quality pharmaceutical manufacturing standards.

References [1] Smekal A., Zur quantentheorie der dispersion. Naturwissenschaften II, 1923, 873–875.

Similarity coefficients:

1 – 0,98

0,98 – 0,85

Fig. 2. The matrix of specificity for the tested materials

1/2012

< 0,85

[2] Cygański A.: Metody spektroskopowe w chemii analitycznej. Wydawnictwo Naukowo-Techniczne, Warszawa, 1997.

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Polish industry | 11

Managenent of waste electrical and electronic equipment in the pharmaceutical industry

Monika Blezień–Ruszaj Specialist for the environmental protection

Equipment mounted in / on the process lines, as well as laboratory equipment (including dryers, coolers, climatic chambers or Laminar Flow and shakers, vortex, microscopes, and the whole plant equipment operating in the pharmaceutical industry with the help of electric current), at some point become a waste that is classified as waste electrical and electronic equipment.

Pharmaceutical companies should develop an appropriate strategy

equipment, put on the market after 1 July 2006, did not contain certain

for management of waste electrical and electronic equipment, so that

hazardous substances, such as lead, mercury, cadmium, hexavalent

the influence of pharmaceutical companies and their activities have

chromium, polybrominated biphenyls (PBB) or polybrominated diphenyl

the least adverse impact on the environment surrounding us. It should

ethers (PBDEs)

realize that both the electrical and electronic equipment and batteries and

The RoHS Directive is directly related to the Directive 2002/96/

accumulators which supply some devices contain hazardous substances

EC on waste electrical and electronic equipment ( WEEE).

which after using and removaling can often be a major threat to humans,

This Directive has been transposed into Polish law of the Minister of Eco-

animals and the environment.

nomy of 27 March 2007 on detailed requirements for the restriction of the

To organize a good system of dealing with electronic equipment in

use of electrical and electronic equipment of some substances which may

the pharmaceutical, you must understand the legal requirements of the

adversely affect the environment (Journal of Laws No. 69 item. 457). The

European Union among others. Directive 2002/96/EC of 27 January 2003.

purpose of the Directive is to reduce the amount of hazardous substances

on waste electrical and electronic equipment, Directive 2002/95/EC dated.

penetrating into the environment from waste electrical and electronic.

January 27, 2003. so. RoHS Directive 2006/66/EC of 6 September 2006.

The WEEE Directive of the European Parliament and Council 2002/96/

on batteries and accumulators. Polish legal scope of the Act provide,

EC dated January 27, 2003 on waste electrical and electronic equipment,

among others Waste Act (Journal of Laws No. 62 item. 628 of 2001. as

is to establish liability. According to the main objectives of the act the

amended), Act on Waste Electrical and Electronic Equipment (Journal of

manufacturer should design and manufacture electrical and electronic

Laws No. 180 item 1495 from 2005. as amended) and the Act on batteries

equipment to take into full account and facilitate their repair, possible

and accumulators ( Journal of Laws No. 79 item 666 of 2009).

upgrading, reuse, disassembly and recycling. The main objective of the Directive is correct and thoughtful management of waste electrical and

Legal scope – guidelines associated with WEEE and batteries and accumulators, which is what an entrepreneur associated with the pharmaceutical industry should know?

electronic products primarily through its separate collection.

Directive 2002/96/EC was introduced into our legislation the Act dated 29 July 2005 Waste electrical and electronic equipment. This Act sets out the requirements to be met by electrical and electronic equipment, as well

The RoHS Directive - (Restriction of Hazardous Substances), from

as the treatment of this equipment in a way that protects human health

January 27, 2003. (2002/95/EC) was published on 13 February 2003.

and life as well as protection of the environment in accordance with the

The directive applies to requirements that new electrical and electronic

principle of sustainable development.

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1/2012

12 | Polish industry Principles of management weee in the pharmaceutical industry: • • • • •

Don’t mix WEEE from household waste Used equipment to put into a treatment facility or the producer – importer of the equipment Don’t disassemble equipment Without holding the used equipment longer than necessary Save

Employees of pharmaceutical plants, research laboratories, laboratory quality control or process lines (including e.g. air-conditioned weighting room, blenders, mixers, rotary tablet – presses, hard capsule filling) every day in operation, electric and electronic equipment (such as control panels, laminar Flow, analytical balances), which at some point become the electro - waste – used equipment.

Separate collection of electro – waste The starting point for the proper management of waste electrical and

Plants for medicines, having in his assumption of the wider

electronic equipment should be their separate collection. This collection

environment, they should pay attention to the emerging electro - waste.

by the Directive is the precondition to ensure adequate for this type of

The main goal of the Act is a selective collection. To live according to the

method of processing waste and recycling, it is also necessary to achieve

law as well as the surrounding environment would create the following

the desired standard of living in the community and the environment.

steps for dealing with WEEE:

The main purpose of the Act is to reduce the amount of waste generated

•

The wastes collected separately

from the equipment and provide appropriate levels of collection, recovery

•

Do not mix hazardous waste (including WEEE) with different types

•

Electro - waste disposal for specialized treatment - list available on

and recycling of used equipment

Waste electrical and electronic equipment.

of waste the www.gios.gov.pl

Devices whose correct operation is dependent on electric currents or the presence of electromagnetic fields in order to work properly and equipment for

WEEE collection systems and batteries and accumulators

generation, transfer and measurement of electric current or electromagnetic

•

At the time when used equipment is being replaced by the new of

fields and designed for use with a voltage not exceeding 1000V for alternating

the same kind, introducing the customer’s equipment shall receive a

current; and 1500 V for direct current classified groups of equipment referred to

form - return of equipment and transfer it to a treatment facility

in Annex 1 to the Act. (Journal of Laws No. 180 item. 1495 of 2005. as amended)

•

Used batteries and accumulators - the end user is obliged to

The pharmaceutical industry plants used electrical and electronic equipment

transfer them to the collector of waste batteries and accumulators

is one of the groups:

Plants of the pharmaceutical industry at a time when the owner of

•

8 - Medical devices with the exception of all implanted and infected

WEEE will give him or report to introducing / collecting, in the next

products and

step chain links the equipment goes to a treatment facility where it is

•

9 - Monitoring and control instruments

for recovery and recycling

•

8.7 analysers

•

8.8 freezers

•

8.10 other appliances for detecting, preventing, monitoring, treating,

Rights and obligations of users of the equipment Plants of the pharmaceutical industry must adapt its policies as a

alleviating illness, injury or disability and

company as well as their conduct to legal requirements, to the time of

•

9.3 thermostats

the WEEE to know how to handle it. Companies may not always realize,

•

9.4 measuring equipment weighing or adjusting appliances for

but instrumentation that are installed on the production halls, which

household or as laboratory equipment

use the productions, production monitoring and subsequent stages

•

9.5 other monitoring and control instruments used in industrial

of the electronic devices. Not all of them are connected to the outlet,

installations (e.g. in control panels

some only examine the successive stages of manufactured products.

This so-called. with battery testers - they also belong to electronic

Electrical and electronic equipment in the Pharmaceutical Industry Works

equipment. As can be seen, the cosmetic industry works is a very

Two categories of equipment:

•

•

Equipment intended for household

•

Equipment other than for households (eqipment that is not normally used in households):

large user equipment.

Plants of the pharmaceutical industry as users of the equipment, batteries and accumulators have both rights and responsibilities associated with them: •

the user equipment is obliged to return used equipment / waste batteries

–

the recipient is a company, industry, enterprises, institutions

and accumulators to the collector or to a pickup point - indicated by

–

the design and features exclusive use in households

the collector

–

not be placed on the market designed for retail buyers

•

Such facilities will meet in the laboratories of pharmaceutical companies in the process lines or on the production halls. The

Do not put used equipment / waste batteries and accumulators together with other wastes

•

when you purchase new equipment has the right to return used

whole production is automated pharmaceutical plants - its effect

equipment to the same type in the amount of 1:1 at the point of sale

is dependent on the flow of electricity (power supplies, batteries,

of this equipment.

or accumulators)

1/2012

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Polish industry | 13

Quality vs. Optimisation Andrzej Wróblewski

Each business sector is unique and different in its own eyes.

The pharmaceutical sector is no exception – it is commonly believed that it is distinguished by QUALITY.

The concept of quality is firmly embedded in the minds of those employed by pharmaceutical companies from the very first day of work.

However correct that might be, this tendency somehow distorts the true image of pharmaceutical business. It impairs rational reasoning and conceals solutions which have been long-proved in other sectors of the economy, such as, in particular, the process of continuous improvement to reduce quality risk along with simultaneous reduction of costs and efforts involved.

In other words:

Maximum quality at minimum costs

Andrzej Wróblewski Born in Poznań, graduate of the Poznań University of Technology, Faculty of Chemical Technology, working in the pharmaceutical industry since 1994, initially as a Production Manager in Polfa Poznań, Surgical Suture Dept., subsequently in the Validation Dept. Following corporate restructuring, Andrzej Wróblewski now works for GlaxoSmithKline. Since LeanSigma implementation in 2001, he has been preoccupied with the streamlining of business processes.

These two concepts are generally perceived as mutually exclusive, which means we must choose quality at the cost of savings or vice versa. But is it really true? Is it possible to implement optimisation programmes without compromising the quality?

workflow to improve its quality. The resulting quality effects may be

Is it true that optimisation programmes inevitably entail the reduction

similar, but are produced by means of different solutions. To be able

of quality? In this paper, I will try to prove that this common belief is

to better comprehend this difference, let us now refer to the idea

in fact false and that correctly implemented optimisation programmes

behind business streamlining programmes. It will be illustrated with the

are able to both, reduce costs and improve product quality.

examples of programmes based on Lean Manufacturing and SixSigma (which I know best). Although the key principles invented by the pro-

QUALITY AND OPTIMISATION are complementary rather than competitive concepts.

gramme developers remain constant, each implementation is tailored to suit each individual business. This is why the approach presented in

There are currently a multitude of performance improvement pro-

this paper may be different from the one you are accustomed to. I am

grammes to choose from. These programmes were created many years ago and have been developed with each subsequent implementation.

Nevertheless, the pharmaceutical sector can be hardly called the leader

Optimisation

or the driving force of optimisation and only rarely takes advantage of the opportunities offered by optimisation programmes. The majority of pharmaceutical companies have been implementing programmes aimed to improve quality. However, only few pharmaceutical businesses decide to use typical “optimisation” programmes.

There is a clear difference between these two. In quality improve-

In this paper, „optimisation” is used as a key word, however, there are different terms expressing the same meaning, such as the traditional „Cost-reduction Programme”, the more ambitious „Process Development”, or concept-related names, such as Lean Manufacturing, TPM or SixSigma.

ment programmes, costs are not considered a priority. On the other hand, optimisation programmes are focused on modifying business

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14 | Polish industry

nevertheless convinced that the discussed relationships are universal

cost) are taken for granted. However, the quality outcome can lead

and independent from the basic assumptions of specific concepts and

to some controversy. Let us refer to the process of completing and

the designed implementation tools.

reviewing production documentation, typically referred to as a Batch

Lean was developed in response to mass production boom in the

Report. This is an important business process accompanying each

second half of the twentieth century. General automatisation took

production. Batch Reports are used multiple times: on production

advantage of technical progress; however, it lacked a commonsensical

completion, at batch release, in complaint reviews, or during audits. The

approach. Process parameters were reaching record levels, but what

consequences of any error, missing data or incoherence are difficult

happened in-between was somehow disregarded, which was perhaps

to anticipate, which makes the process critical to quality. The most

the main source of problems and losses. Also, there was a major

obvious solution would be to increase the number of control points:

change in the mentality of customers across the world: they expected

documentation verification by another person, a foreman, production

equal, yet individual approach. Lean discovered the potential of flexible

supervisor, QC, or QA. Consequently, what we get is a pyramid of

process management to deliver products customized to contemporary

fuzzy responsibilities: employes at each subsequent process level

quality and price expectations. In Lean projects, time is the main driving

become less involved in quality control, believing that all quality issues

force for changes. A typical Lean project consists in simplification

have been already dealt with earlier in the process. Nevertheless, the

or elimination of redundant process components. As a result, the

same approach is adopted by people involved in early QC stages.

process can be implemented faster, it consumes fewer resources

Lean has a different approach - it limits the number of control points

and provides better quality. The first two parameters (lead-time and

down to minimum. With the absence of a complex process structure,

OVERALL YIELD vs SIGMA (Distribution Shifted 1.5s)

SixSigma effect # of Parts (Steps)

Lean effect

1

±3s

±4s

±5s

±6s

93.32%

99.37%

99.9767%

99.99966%

7

61.63

95.73

99.839

99.9976

10

50.08

93.96

99.768

99.9966

20

25.08

88.29

99.536

99.9932

40

6.29

77.94

99.074

99.9864

60

1.58

68.81

98.614

99.9796

80

0.40

60.75

98.156

99.9728

100

0.10

53.64

97.70

99.966

150

39.38

96.61

99.949

200

28.77

95.45

99.932

300

15.43

93.26

99.898

400

8.28

91.11

99.864

500

4.44

89.02

99.830

600

2.38

86.97

99.796

700

1.28

84.97

99.762

800

0.69

83.02

99.729

900

0.37

81.11

99.695

1000

0.20

79.24

99.661

1200

0.06

75.88

99.593

3000

50.15

98.985

17000

1.91

94.384

38000

0.01

87.880

70000

78.820

150000

60.000

Source: SIX SIGMA RESEARCH INSTITUTE Motorola University, Motorola Inc. The figure illustrates the correlation between process strength (capacity, s - sigma), and its complexity (number of process stages), as well as process performance (percentage of in-specification products). A process composed of the minimum number of stages (Lean effect) and providing the maximum process capacity (SixSigma effect) yields the best results.

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Polish industry | 15

each signature involves a considerable responsibility burden. The

For example, moisture measurements in granulates are taken to

quality of work is easier to manage. The overall system is much more

determine end point of the drying process. Moisture balances are used

effective, which always improves quality. This is a typical characteristic

to measure loss on drying, which allows to calculate moisture content.

of a Lean project which changes the scope of responsibilities. The

The weighing process involves relatively insignificant variability, and

same approach can be implemented in more technical environment

the overall measurement operation should not result in any significant

by means of SMED (Single Minute Exchange of Die) to optimise

variability. However, loss on drying can be affected by a number of

set-up changes. This process is growing more and more important

factors. First, the measurement process starts with sampling, which

as production now needs to deal with the growing number of short

can be affected by, in particular: pre-sampling granulate exposure time,

runs, which involves frequent changes of set-up, particularly in the

local environmental parameters, sampling place, sample mass, texture

filling and packaging line. The filling/packaging involves considerably

of the sampled granulate, type of packaging, sample protection, the

high risk of contamination, which makes the working standard critical.

time between sample collection and measurement, etc. Professional

Just like with the Batch Report, there are two possible solutions. The

analysis should identify at least several potential variability factors.

number of control points can be increased, which theoretically limits

Another task would be to neutralize their effects.

the risk of contamination. However, the process quality was shown to

Loss on drying measurements are only a small fraction of the overall

improve only for a short span of time, and in the longer perspective, it

production. When analysing the whole production, a considerable

was found to have a neutral or even negative impact on quality. These

number of other variability factors can be identified.

negative consequences can be explained by process complexity, resulting in the higher risk of errors. The only definite consequence

How can variability attributed to specific factors influence the quality?

is that the process of set-up change becomes longer, and therefore

Quite obviously, variability has a negative impact on quality. The

less effective. Process optimisation is an alternative solution. In this

higher the reliability caused by specific factors, the higher the number

particular case, to optimize the process would mean to arrange and

of out-of-specification results. Randomness and the accompanying

schedule particular components of set-up change and to assign

variability factors can have a mutually intensifying or balancing effect

responsibility for the implementation of each process element. In

to produce results which are quite unexpected. As a result, batches

this case, SMED would be the first-choice optimisation method. In

manufactured according to identical technological regimen can produce

the end, the set-up change becomes more powerful and, at the same

significantly different test results. The inability to identify the sources

time, it consumes much fewer resources. If particular set-up change

of variability, and in consequence, lack of variability control can cause

operations are standardized with a clear responsibility assignment,

serious quality issues, including batch failure. PAT (Process Analytical

the risk of contamination becomes much lower.

Technology) can be a remedy as it translates the idea behind SixSigma

As the two examples show, Lean is mainly interfering in process organization and management. On the other hand, process optimisation is handled by SixSigma, which is assumed to be more quality-related.

into the reality of pharmaceutical production.

Let us now decide if optimisation programmes are implemented at the cost of quality.

However, it employs a different approach to quality issues as compared

I think the answer to this question is no. Yet, every optimisation

to other quality programmes. It attributes bad quality to process

programme needs to be carefully planned and prepared. Apart from

variability in the broad sense of the term. Variability can be caused

technical know-how, cultural support appears essential, meaning the

by raw materials (natural resources in particular), the process itself

business culture, the readiness to embrace changes. What we fear is

(lead-time and temperature parameters, etc.), as well as human factors

sometimes irrational and based on our expectations or past experien-

(manual operations, etc.). The less changeable the process, the lower

ces. It is perfectly understandable; nevertheless I am convinced that

the risk of out-of-specification products. SixSigma assumes a target

correctly implemented optimisation programmes can make production

quality level corresponding to 3.4 defective parts per million (PPM).

faster, cheaper and better.

This means there can only be 3.4 out-of-specification tablets per million

Just like any other market sector, the pharmaceutical industry is

tablets produced. I guess that the SixSigma quality levels would satisfy

governed by the rules of free-market economy, where the decision-

any QC Department. The relationship between variability and quality

-making is mainly based on competition. In automotive and electronic

can be best illustrated with the following example:

industry, optimisation programmes are the precondition for successful

Let us now consider the problem of variability attributed to measu-

business. With relatively low mark-ups and closer customer-brand

rement systems. In theory, measurement systems are only used for

identification, customers have become the main driving force of

checking, and not influencing product quality. The reality is different.

changes and business decisions.

Depending on the local conditions and production stage, measurement

In view of the foregoing, we should perhaps ask ourselves the

systems can be decisive for the process and its assessment. Any

question: â&#x20AC;&#x153;How much longer can the pharmaceutical market perceive

measurements subject to significant variability affect the whole process

optimisation as a threat to product quality?â&#x20AC;?.

to the extent which can be difficult to estimate.

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16 | Polish industry

The changes in interpretation of the scope of the supplementary protection certificate (SPC) for medical products Izabela Milczarek Patpol European and Polish Patent and Trade Mark Attorneys

The reasons for introduction of the SPC Although patent protection lasts 20 years from the filing date of the

for plant protection products was introduced later by Regulation no

application in the Patent Office, the effective patent term, defined as time

1610/96 issued by the European

period for which a product is marketed with a benefit, may be significantly

Parliament and Council of July

shorter. In many fields, the commercialization of the invention takes

23, 1996. Currently, the matter

about the same time or less than patent protection acquisition. There are,

of supplementary protection

however, also areas in which the process of introducing a product into the

certificate for medicinal products

market takes much more time, because before such product is placed on

is regulated by Regulation no

the market, the regulatory authorities have to issue a marketing approval.

469/2009 from May 6, 2009.

This requirement is relevant especially for the pharmaceutical industry, in which marketing authorization of a new drug is connected with conducting tests on the animals and later clinical trials on human beings, in order to

SPC characteristic In order to identify the scope of the SPC in an

prove its safety and efficiency. Sometimes, such a process lasts as long as

appropriate manner two essential definitions were introduced in

8 to 12 years from the filing date. Consequently, in case of a pharmaceutical

the Regulation. One of them is a definition of “a medicinal product” and

product, the period of effective protection is shortened significantly and,

the other is a definition of “a product”. The medicinal product should be

for example, instead of 20 years it only lasts 10 years. Similar situation is

understood as “any substance or combination of substances presented

observed in the chemical industry for the plant protection products, such as

for treating or preventing disease in human beings or animals and any

herbicides and insecticides, which also have to be subjected to many tests

substance or combination of substances which may be administered to

and examined in respect to their toxicity towards workers applying them

human beings or animals with a view to making a medical diagnosis or

and food crops, before they are allowed to use. Carrying out of the required

to restoring, correcting or modifying physiological

investigation is connected with big expenses, which should be returned

functions in humans or in animals”, while the product

to the patent holder. However, the entire refund of the costs would not be

means “the active ingredient or combination of

possible in the case when the effective patent term duration is shortened.

active ingredients of a medicinal product”.1

History of introducing SPC regulations

which is an active substance of the medicinal product for

Therefore SPC provides protection for a product, On 18 June of 1992 the EC Council issued Regulation no 1768/92

which marketing authorization was issued. An SPC may be granted for

creating supplementary protection certificate (SPC) for medical products

5 years maximum (in the case of pediatric population there is a possibility

in order to compensate for the loss of patent protection period for phar-

to extend the SPC duration for additional 6 months) and it takes an effect

maceuticals, whose introduction into market is delayed by the necessity

from the moment of patent expiry. SPC can be applied for within six

of obtaining marketing approval. Regulation concerning SPC came into

months from either the date of the first marketing authorization or from

force on 1 January 1993. Extension of the supplementary protection

the date of patent grant, whichever decision is issued later. According to

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17 the current Regulation 469/2009 SPC confers the same rights, limitations

Court of Justice (ECJ) in the case of C-392/97 Famitalia Carlo Erba Sri.

and obligations as the patent on which it is based. In addition SPC is

This company was a patent holder of patent for idarubicin, a method

limited only to the product covered by the marketing authorization for the

of manufacture thereof and pharmaceutical composition comprising

corresponding medicinal product and for any medical use of this product

thereof. This company has obtained a marketing authorization for the

that has been authorized before the expiry of the certificate (art. 4 of the

medical product called Zavados. Idarubicin hydrochloride, the active

Regulation 469/2009).

substance of this product, was disclosed also in the basic patent. When the company applied for an SPC for a product defined as “idarubicin

The scope of protection resulting from the SPC

and salt thereof including idarubicin hydrochloride” it was granted the

Case of Draco AB

supplementary protection certificate only for “the medicament Zavedos

The most important question related to the SPC is how to establish what

containing idarubicin hydrochloride as an active ingredient“. Famitalia

is the scope of protection resulting from the SPC. As the principles of the

began appeal proceedings before the Federal Patent Court and applied

SPC were developing, the interpretations concerning its scope have chan-

for the supplementary protection certificate for “idarubicin and salt

ged. At first, it was considered whether the SPC protection extends to an

thereof including idarubicin hydrochloride” or “idarubicin and idarubicin

active ingredient in all possible formulations, or covers only one particular

hydrochloride”. The request was rejected and Famitalia lodged an appeal

formulation for which the marketing authorization has been obtained, which

against this decision to the Highest Federal Court, which has turned to

is a basis for applying for the SPC. An example of the case in which this

ECJ for interpretation. Based on the ECJ ruling it was established that

issue was considered was Draco AB case. The first marketing authorization

supplementary protection certificate may also comprise other product

for the anti-asthmatic drug – budesonit in the form of aerosol was obtained

forms, provided that they are protected by the basic patent, and not only

by Draco AB in 1981, i.e. before the SPC regulations became effective.

the form for which the marketing authorization was obtained.

In 1989 the company obtained the marketing authorization for the same

In the preamble of Regulation 469/2009 it has been emphasized that the

drug, but in a form of micronized powder (a dry-powder inhaler).

protection period obtained based on the SPC should guarantee a suitable

English Patent Court in the case of Draco AB upheld refusing

and efficient medical product protection to promote the research in the field

decision issued by the UK Patent Office. While applying for

of pharmacy. Innovation is crucial to the pharmaceutical industry, because

SPC, Draco referred to the later marketing authorization.

the entire society is interested in increasing the level of public health and

English Patent Court refused granting SPC based on the

availability of better and better medicines. However, current development

argument that the marketing authorization submitted

of research and formation of more and more complex products used for

in support of the application for a special protection

the treatment of human beings lead to constant uncertainty with respect

certificate was not the first marketing authorization for this

to the scope of protection. Medicinal products, which are placed on the

product. The earlier marketing authorization concerned

market often include many various active ingredients with very complicated

the same active substance as in the second marketing

therapeutic activity (eg. combined vaccines), which are administered

authorization. Therefore the requirements of Article 3(d) of

for a patient’s convenience by the means of a single medical product.

Regulation no 1768/922 according to which the first marketing

Therefore it would be contrary to the intention of the Regulation 469/2009

authorization has to be the basis for applying for the SPC,

to refuse grant of the SPC to the holder of a basic patent covering one of

were not fulfilled. The English Patent Court admitted that

the novel active agents, in a situation when the medicinal product, in the

the scope of protection should be strictly confined to the

form intended for sale, includes more active substances. The subject of

active substance of the medicinal product for which the

this regulation is to provide such a protection, which would encourage the

first marketing authorization was issued, regardless of

pharmaceutical enterprises to do further research and development work

the form in which the active substance was included.

in the field related to health of the society. If the patent holders are forced to put on the market only the products containing active substances in

Case of Famitalia Carlo Erba Sri (C-392/97)

the form as claimed in the basic patent, it would lead to the monovalent

A question which still remained without an answer

medicinal product development, which would not be advantageous from

was whether the product entitled to protection is the active

the social point of view. Therefore, many efforts were put to obtain the

ingredient in the form of a specific salt, for which the marketing

legal interpretation of this issue.

authorization was issued, or whether the protection could be extended to all its salts, esters, etc. Limiting the product to a specific form would seem without merits. Regulation No 1768/92 has left this question without a binding answer. However, Regulation 1610/96 extending the

Cases C-322/10 and C-422/10 On the 24 November 2011 the Court (Fourth Chamber) issued decision in case C-322/10.

SPC grant to the plant protection products has specifically indicated

In the case C-322/10 on 26 April 1990, Medeva filed an application

in the preamble that if a basic patent provides protection to salts and

for a European patent, registered by the European Patents Office under

esters, the same scope of the protection has to be applied to the SPC,

EP number 1666057, for a method for the preparation of an acellular

even if the marketing authorization was issued for a specifi c form.

vaccine against Bordetella pertussis, also known as ‘Pa’, consisting of

Such an interpretation has been confirmed by a ruling of the European

a combination of two antigens as active ingredients, namely pertactin

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18 | Polish industry and filamentous haemagglutinin (‘filamentous haemagglutinin antigen’),

•

Whether above mentioned regulation, especially Article 3 (b), permits

in such a ratio as to provide a synergistic effect in vaccine potency. The

the grant of a supplementary protection certificate for a single active

patent was granted by the EPO on 18 February 2009 and expired on

ingredient or combination of active ingredients when:

25 April 2010. Medeva filed five SPC applications for the purpose of

a) basic patent in force protects this single active ingredient

protection extension for vaccinies DTPa-IPV/HIB covering diphtheria (D),

or combination in the meaning of Article 3(a), and

tetanus (T), whooping cough (Pa), poliomyelitis (IPV) and/or meningitides

b) medicinal product containing in addition to the single active

caused by Haemophillus influenza (HIB). In support of these applications

ingredient or combination of active ingredients also other active

Medeva submitted market authorizations issued by the German, French

ingredients is the subject of the valid authorization granted in

and United Kingdom authorities for medical products: Infannix , DTCaP,

accordance with Directives 2001/83/EC or 2001/82/EC, which

Infanrix IPV, Infanrix IPV+HIB, Infanrix Quinta, Pediacel and Repevax.

is the first marketing authorization that places that single active

Each of this medical products besides peratactin and fi lamentous

ingredient or combination of active ingredients on the market?

haemagglutinin contained from 8 to 11 other active components. Comptroller General of Patents, Designs and Trade Marks (UK), defined next

The first five questions were asked to establish how the Article 3(a) of

briefly as a Patent Office, refused to grant SPC in relation to four of these

the Regulation 469/2009 should be interpreted. Does this article object the

applications (SCP/GB09/015, 09/016, 09/017 and 09/019) arguing, that

granting of SPC if among the active ingredients indicated in the application

more active ingredients were indicated in the applications than in the

there are additional active ingredients, which are not mentioned in the

claims of the basic patent. Therefore in accordance with Article 3 (a) of

patent claims of the basic patent.

Regulation No 469/2009 they are not protected by the basic patent3.

The sixth question aimed to establish whether or not Article 3(b) of the

The Patent Office found, with reference to the fifth application (SPC/

Regulation 469/2009 may be interpreted as precluding from SPC grant in a

GB09/018), that although the active ingredients were the same in the

situation when a mixture of two active corresponds to the mixture identified

patent claims and in the SPC application, marketing authorizations

in the patent claims of the basic patent, but the medicinal product whose

submitted in support of that application did not meet the requirements

marketing authorization was presented in support of the SPC application,

of Article 3(b) of the above regulation4, inter alia because they related to

contains also additional active substances not mentioned in the claims

medicinal products containing 9 active ingredients, i.e. to the vaccines,

further to the said mixture.

which did not only contain the active ingredients specified in the SPC

In the case of the five questions considered together, the Court of

applications and in the patent claims. Medeva appealed against this

Justice stated, that Article 3 (a) of Regulation No 469/2009 objects to the

decision to the High Court of Justice (England and Wales), which rejected

grant SPC with respect to active ingredients, which were not mentioned

this appeal by judgment of 27 January 2010. Medeva appealed again

in the patent claims of the basic patent. Whereas in the response to the

and this time to the Court of Appeal (England and Wales) (Civil Division)

sixth question, the Court of Justice stated, that the Article 3(b) of the above

suspended the proceedings and turned to the Court of Justice with the

mentioned regulation must be interpreted in such a way, provided that the

following questions:

other requirements foreseen in this article are fulfilled, that it does not object

•

In the lack of the harmonization of patent law what is meant by the

the SPC grant for a combination of two active ingredients corresponding to

expression “the product protected by a basic patent in force” used in

the combination defined in the patent claims, if the medicinal product for

Article 3(a) of the Regulation No 469/2009 and what are the criteria for

which the marketing authorization is submitted in support of the application

considering this matter?

for a special protection certificate, contains also other active ingredients.

•

Whether or not in case like the present dispute involving a medical product comprising more than one active ingredient are there any

•

Similar verdict was issued by the Court of Justice (Fourth Chamber) in case C-422/10 (case of Georgetown University).

further or different criteria for determining if “the product is protected

Therefore it can be expected, that the Polish Patent Office will take

by a basic patent” according to Article 3(a) of the above mentioned

into account above interpretations of the Court of Appeal while granting

regulation and, if yes, what are they?

the supplementary protection certificates and it will be possible to obtain

Whether or not in case like the present dispute, which involves

supplementary protection certificate on the basis of the marketing autho-

a medicinal product being a combined vaccine, exist further or different

rization for a drug containing additional active ingredients, which are not

criteria of determining if “the product is protected by a basic patent”

a subject of the claims of the basic patent.

according to Article 3(a) of the above mentioned regulation and, if yes, what are they?

•

Whether or not for the purpose of Article 3 (a) a combined vaccine consisting of many antigens is “protected by a basic patent” if one antigen of the vaccine is “protected by the basic patent in force”?

•

1 2

Whether or not for the purpose of Article 3 (a) a combined vaccine

3

consisting of many antigens is “protected by a basic patent” if all

4

antigens directed against one disease are “protected by the basic patent in force”?

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Regulation (EC) No 469/2009 of the European Parliament and of the Council the authorization referred to in (b) is the first authorization to place the product on the market as a medicinal product (a) the product is protected by a basic patent in force; a valid authorisation to place the product on the market as a medicinal product has been granted in accordance with Directive 2001/83/EC or Directive 2001/82/EC, as appropriate;

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production | 19

When PAT stimulates innovation Dariusz Figiel Endress+Hauser Polska Sp. z o.o.

Since the FDA introduced the PAT initiative back in 2002, several steps have been taken by both drug manufacturers and suppliers of the critical process measuring instruments. Beyond these steps, new guidelines and standards have been created or updated, allowing the cultural evolution that is unavoidable when using such an approach. Quality risk management is integrated in the process for assessment, control and communication, which means that the impact of the variability is understood by the pharmacist (impact on the patient) and the supplier (implementation of the right measuring control strategy). The expected key innovation is the capability of suppliers to demonstrate that the reliability of the measurements induce the robustness of the process and consequently reinforce the quality of the drug, ultimately benefitting the patients.

Process Analytical Technologies (PATs) have been defined by the

process will then clearly appear. They have to be selected and

FDA as systems for analysis and control of manufacturing processes

mirrored regarding the targets. The selection of the data in question will

based on timely measurements of critical parameters and performance

generate project priorities. Some of the priorities will appear after the

attributes to assure acceptable end product quality at the completion

risk analysis. Some others are directly linked to the implementation of

of the process. Process analytical technology involves optimal appli-

the measurements and control of the data, complexity of the relevant

cations of process analytical chemistry tools, feedback process control

implementation, cost of the project as well as final benefit issues

strategies, information management tools and/or product/process

(process robustness) before any decision is made. This first step

optimization. The term analytical is viewed broadly to include chemical,

represents the most critical one simply because it will have a direct

physical, microbiological, mathematical and risk analysis conducted in

impact on the optimization approach. For doing this, the key is to create

an integral manner. In two main steps of the full PAT innovation, the first

a competent team. Each team member shall have in-depth knowledge

one revolves around the process itself and the second one focuses on

of the most critical steps of the process in great detail. The selection of

the implementation of the relevant measurements and control system(s).

the team members within an organization according to this aspect, must also include expertise on quality (any quality concern), science and

First step: A more robust process

attention to potential obstacles that may exist locally. As a team they will

The process as a whole has to be understood because the whole

be able to identify the weaknesses of the process and identify where the

process is involved. This responsibility lies with the drug manufacturer.

process variability can be improved and existing sources of errors can be

What is to be dealt with and how to focus on the biggest gaps has

eliminated. A list of identified measurable and controllable parameters

to be established before proceeding with the risk assessment.

influencing the quality of the final product will be drawn up. Statistical

A selection of the most beneficial aspects and targets can then be

process control (SPC) and/or monitoring of the data in question can

selected after having conducted this process overview. The critical set

eventually be assessed and performed before any decision is taken. At

of data to be collected and analyzed for the improvement of the

this stage the question of how to implement the process improvement will

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20 | production

Picture 1. The involved process has to be understood. This belongs to the responsibility of the drug manufacturer

be answered with: by selection of the adequate process measurements,

management of the documentation has to also be done according to

control and monitoring systems.

the guidelines. So the supplier has to objectively provide evidence that the specific requirements from the drug manufacturers are

Second step: process control and monitoring

fulfilled. Cost reductions are generated simply because by relying on

It becomes urgent to eliminate any uncertainties which have

a partner’s quality system and documentation, lots of tests become

been identified. True process optimization being the challenge, the

redundant and need no longer be duplicated, thereby saving on both

implementation of the measuring points and the controlling and

costs and time. Project management tasks undertaken by the supplier

monitoring strategies have to be conducted according to the existing

(according to GAMP5) as well as allocation of budgets and resources for

guidelines. The ASTM E 500 and GAMP5 have to be used. They are

integration of the equipment allow manufacturers to focus on their core

the most universal guidelines and standards to–date. They include

competencies. Experience has shown that this team money and trouble

the risk based approach which verifies the patient protection while

when the partner has adopted the GxP’s approach as a golden rule.

facilitating the engineering and quality principles. In other words, the risk based but also the science based approaches will directly impact

Benefits

the design, the specification and also the verification of the equipment,

Team working efficiency has shown that the myth becomes reality. This

including the process measuring instruments and the control systems

is particularly crucial for complex process applications. The patient is the

for manufacturing the drug. This impacts any equipment that can

very first one to benefit from the greatly increased protection thanks to

potentially affect the quality of the drug which is produced (quality

the more consistent quality of the drug. This is truly the ultimate objective.

by design).

Encouraging drug manufacturers and suppliers to closer

The second “set of benefits” are enjoyed by the drug manufacturers: •

Risk assessed in a positive fashion (expected skills and experiences

includes the GEP’s (Good Engineering Practice). This is a precondition

•

Money is saved through peace of mind from the production side

which is verified by the manufacturers with supplier assessments

•

Robustness of the process improved

and audits being conducted. Documentation is one key (verification

•

Improved quality and better process variability

documentation). The manufacturers expect to use the documentation

•

Uncertainties eliminated

created by the suppliers instead of producing it themselves. The

•

Confidence in working with the new PAT approach

collaboration is needed. Potential suppliers have to be in a position to demonstrate that they have developed a Quality System which

1/2012

put together) and errors eliminated as much as is humanly possible.

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production | 21 •

Better knowledge of critical process parameters measurement by

systems. The pH measurement could be delivered as fully

teams working with their partner.

automated system for measuring, cleaning and calibration. World leading suppliers of instruments for process automation could

The final group of benefits is generated by the contribution of the

offer such a devices. The system contains a changeable armature

partner:

a mounting plate for the control valves, a control cabinet for the

•

Projects conducted according to the rules: efficiency and execution

solenoid valve island, a control cabinet for the buffer solution and

•

Cost reductions: duplications of tests avoided

the control unit based on a process logic control (PLC) mounted

•

Time reduction: competencies and knowledge of technologies,

in a separate control cabinet. The pH process value is measured by

instruments and control/monitoring systems

special pH electrode dedicated for pharma processes.

• • •

Documentation delivered with the systems leads to simplifying the management of the project while optimizing the expenses

The customer benefits:

High experience in qualification, verification and calibration leads to

•

No waiting time for results from the lab

the best projects and fits the manufacturers’ expectations

•

Online measurement leads to direct engagement into the process

Latest rules implemented for instruments and control or monitoring

•

Continuous production.

systems.

Picture 2. A complete, fully automated pH measuring device guarantees continuous process safety in pharma industry

Example: pH measurement, including on–line calibration

Summary What is the secret of successful implementation of PAT in the end?

The fermentation process is so common but also so critical

Based on the teamwork abilities and capabilities of both parties, the

that it justifies the example we’ve selected for illustrating this

drug manufacturer and the supplier, the partnership mentality induces

paper. Variety of pharmaceutical production facilities (including

several new keys:

bio–production) are highly concerned. It is mandatory to strictly

•

Regarding the revenue, the improved quality, the better speed to

monitor all the critical process parameters and to control them. Let’s

market and an improved flexibility which contributes to opening up

take the example of the pH measurement and its verification and

new markets for the manufacturer

calibration. Off line analysis and calibration can easily be replaced by

•

provement comes from the fact that the correct critical data is always

The competence and knowledge on new process style, improved and innovative, including new technologies and tools

on–line calibration when needed or in a systematically way. The im•

Reduced operating costs (fewer errors) while minimizing the risk.

available in real time, leading to decreasing operating costs while increasing the robustness of the process and the quality of the product. This optimization is reproducible for any similar application and

These three above–mentioned vectors represent some fundaments of a measurable innovation process.

is established through comprehensive monitoring and control

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22 | production

Preparing a coating mixture with Eudragit E PO – technological problems and suggested solutions Anna Kluk, Małgorzata Sznitowska Departament of Pharmaceutical Technology, Medical University of Gdańsk

Coating is a technological process based on covering the surface of solid drug forms, i.e. tablets, capsules or pellets, with a polymer coat that is responsible for the protection of drug cores and substances contained inside against detrimental influence of air, moisture and light.

Moreover, it plays a role of visual appearance improver. Coats made of ap-

ratio: 60:40; marketed product: Eudragit 12.5) or aqueous colloidal dispersion

propriately selected polymers may also modify rate and site of active substance

prepared from Eudragit E PO in the form of powder [1,3]. However, due to a

release from a drug form. The coat may exert a significant effect on the right

poor Eudragit E solubility in water, obtaining a colloidal solution out of the latter

course of a therapy as very frequently it gives colour to tablets, thus enabling

product requires solving a series of technological problems.

their identification by patients and contributes to their easier swallowing. In the

On its website Evonik Industries, an Eudragit manufacturer, has presented

case of non-modified drug forms coating often serves disguising an unpleasant

exemplary compositions of coating mixtures for respective types of metacry-

flavour or odour of active substances contained in the tablet. Provided the

lates including description of their preparation. The composition of coating

coat is not designated for drug release modification, its manufacture uses

mixture for Eudragit E PO has been shown in the table 1.

mainly water soluble polymers such as polyvinyl alcohol, methylcellulose,

The procedure presented by the manufacturer makes the process division

hypromellose, caboxymethylcellulose sodium salt, polyethylene glycol 6000

into several stages as follows:

or povidone. Nowadays, also dimethyl aminomethacrylate (Eudragit E) is more

•

and more commonly used as a flavour disguiser.

Preparing a colloidal dispersion of the polymer using UltraTurrax stirrer – a gradual successive addition to water of the following: sodium lauryl

Eudragit E is a cationic copolymer of three methacrylic acid esters, namely:

sulphate, stearic acid and Eudragit E PO. Subsequent portions are to be

dimethylaminoethyl, butyric and methyl [1]. This polymer is soluble exclusively

added until the polymer stops accumulating on the dispersion surface.

•

at acidic pH (Fig. 1).

The presence of dimethylaminoethyl functional groups enables the conversion of polymer into a salt in acidic environment. Therefore, Eudragit

Addition of talc (and a dye) to the dispersion and a 30 min homogenization using UltraTurrax stirrer.

•

Straining the suspension through an 0.5 mm sieve.

E dissolves merely at pH<5 and stays insoluble at higher pH values. Such properties make the dimethyl aminomethacrylate coat dissolve at acidic pH in

The preparation of coating mixture according to the above scheme seems to

the stomach ipso facto allowing for a rapid tablet disintegration. Concomitant

be easy. However, in fact the simplified and shortened instruction brings the risk

Eudragit E resistance to dissolution at neutral pH is the reason for stability of

of incorrect dispersion performance virtually at every stage of its preparation.

the coat in the mouth (pH of human saliva is 6.8-7.2 [2]). Hence, it constitutes

The manufacturer’s instruction does not indicate in any way that the

an effective barrier between taste receptors and substances contained in the

presented coating mixture should be divided into two phases (polymer and talc

tablet. The effect of taste disguise has been observed with coat thickness

dispersion, respectively), which, with respect to method of their preparation,

as small as 10 µm [3]. An additional advantage of Eudragit E is a relatively

ought to be prepared separately and pooled at a final stage. This requires the

high plasticity and flexibility of obtained coats so that the use of plasticizers

distribution of designated amount of water between both phases. Using all

is not required [3]. In relation to an intensive development of the drug forms

the water for the preparation of Eudragit colloidal dispersion would therefore

disintegrating in the mouth, Eudragit E is more and more commonly used in

make it impossible to prepare talc suspension and its homogenization. This

the unpleasant taste disguise technology.

occurs because an appropriate talc dispersing needs the use of UltraTurrax.

Coating with dimethyl aminomethacrylate may take place using an organic

Thus, the addition of such a substance into the polymer solution would entail a

solution of the polymer in the mixture of isopropyl alcohol and acetone (mass

need for homogenization of the whole dispersion. Despite the fact that Eudragit

CH3

CH3 H3C

N

CH2

O

C

CH2

O

CH3

CH3

C

C

O

O

C4H9

O

CH3 H+ CH3

O

CH3

H3C

+N H CH2

O

C

CH2

CH3

O

C O

CH3

O

C4H9

C O

O

CH3

Fig. 1. Structural formula of Eudragit E and its dissociation in acidic pH

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23

Ingredient

Quantity to Quantity be weighted based on dry [g] coat [%]

Function

because after adding the whole amount of Eudragit this stage needs approx. 3-4 h additional stirring for the reaction between polymer and the acid to complete. If a used stearic acid is characterized by a large particle size, the reaction proceeds

Eudragit E PO

85,7

57,1

Polymer

Sodium lauryl sulfate

8,6

5,7

Emulsifier

Stearic acid

12,9

8,6

Salt former

Talc

42,8

28,6

Filling substance

Water

850,0

–

Diluent

fluid (after approx. 2 hours of stirring). This visual change is to be indicative of

Total

1000,0

100,0

–

a chemical reaction occurring in the dispersion between polymer and stearic

slowly and the stage of the colloidal dispersion formation may prolong itself even by 12 h. A properly performed Eudragit E PO dispersion should take the form of an iridescent colloidal solution. Only after the obtainment of such a dispersion

Table 1.

form, is adding following ingredients of the coating mixture possible. Yet, Evonik technologists assure that the prepared dispersion may be also used for the coating at an earlier stage when it takes the shape of a ‘self-clearing’ yellowish

acid molecules. As early as at this very stage the dispersion may be sufficient

E, as the only representative from the family of metacrylates, does not reveal

for the obtainment of an appropriate quality coat.

any sensitivity to mechanical stirring, yet the use of UltraTurrax is not indicated

Talc is a filling substance in the given recipe. It should be sieved through

owing to the presence of sodium lauryl sulphate in the solution. This chemical

a sieve (e.g. 0.5 mm mesh diameter) and subsequently dispersed separately

compound is a surface-active agent, giving rise to a strong frothing of the

in the remaining amount of water (250 parts) with an addition of a dye and

dispersion once intense homogenization is instituted. As a result, a stable froth

homogenized with the use of UltraTurrax stirrer for approx. 30 min under

arises. It is hard to be removed even by the addition of anti-frothing agents.

laboratory conditions. Once both phases (talc suspension and Eudragit

The first stage of solving this problem is dividing the amount of water given

dispersion) are pooled, the whole liquid should be poured through a 0.5 mm

in the recipe between polymer dispersion and talc suspension, preferably in

mesh sieve and constantly stirred both before and during the coating process.

Such an approach should guarantee an adequate quality of the obtained

600 g : 250 g ratio per each 1000 g coating mixture.

Furthermore, in order to prepare the stearic acid dispersion in sodium

coat both with respect to its aesthetics and its efficacy as for disguising an

lauryl sulphate solution followed by the polymer dispersion, the use of regular

unpleasant taste of active substances. Baring in mind the above factors, a

tips with the UltraTurrax stirrer should be avoided. For this purpose, Eudragit

protocol for a proper performance of coating dispersion with Eudragit E PO

manufacturer recommends the application of special anti-frothing tips for

ought to be the following:

the UltraTurrax or Silverson stirrer. Their unique construction prevents from

•

Dissolving lauryl sodium sulphate in 600 parts of water using an

•

a. Raising solution temperature up to approx. 50-60°C and gradual

electromagnetic stirrer.

a strong frothing of homogenized dispersion. However, if someone does not have such a device they can use an electromagnetic stirrer for preparing the

dispersion of micronized stearic acid or

coating mixture. In the case of micronized stearic acid, e.g. Stearic Acid Powder NF, Mallinckrodt, its appropriate dispersion is achievable through a gradual

b. Raising solution temperature up to approx. 70°C and gradual

addition of the substance onto the surface of sodium lauryl sulphate solution

addition of stearic acid (“oil-in-water” emulsion formation) followed

while quite an intense stirring (approx. 300 rpm) takes place. Fast dispersing

by temperature drop to 50°C.

with no association of acid molecules is also obtainable through raising the

•

causes the melting of stearic acid particles and the formation of oil phase that

• • •

liquid (>50°C) would induce the precipitation of insoluble polymer aggregates.

Blending both phases (polymer dispersion and talc suspension), straining the suspension through an 0.5 mm sieve.

should remember about reducing the temperature below 50°C prior to adding Eudragit as the polymer is sensitive to high temperatures. Adding it to a hot

Preparing a talc suspension in 250 parts of water (with possible addition of a dye) and its homogenization using UltraTurrax stirrer (approx. 30 min).

of coating mixture and is beneficial in such a case when the used stearic acid features a large particle size (above 500 µm). However, using this solution you

Constant stirring with the electromagnetic stirrer until an opalescent solution is achieved (3-12 hrs).

when intensely stirred and in the presence of sodium lauryl sulphate leads to the formation of oil in water emulsion. This modification accelerates the formation

Gradual addition of Eudragit E PO – subsequent portions are added until the polymer stops accumulating on the dispersion surface.

process temperature to approx. 50-60°C. A higher temperature (approx. 70°C)

•

Constant stirring with the electromagnetic stirrer during the coating process.

An adequate dispersion of stearic acid allows for its reaction with Eudragit E with the formation of a soluble salt form. Consequently, the particle size in

References

the dispersion gets reduced to approx. 60-80 nm [3], which brings about the

1. Rowe R. C., Sheskey P. J., Quinn M. E.: Handbook of Pharmaceutical

formation of an iridescent colloidal solution. In order to effectively disperse the polymer, Eudragit ought to be added no earlier than after a complete dispersion or emulgation of the stearic acid; its consecutive portions being introduced

Excipients , 6th edition, Pharmaceutical Press, London, 2009 2. Janicki S., Fiebig A., Sznitowska M., Farmacja stosowana [Applied Pharmacy], PZWL Warszawa, 2002

slowly and gradually only after the preceding polymer portion has stopped

3. Eudragit Application Guidelines, Evonik, 2009

accumulating on the suspension surface. The Eudragit manufacturer ensures

4. Shawn A., Kucera; Eudragit E PO: The pow(d)er for superior formulation

that the stage of obtaining a colloidal Eudragit E dispersion prepared in this way

options; training by Evonik Industries company, 2009

lasts about 1 hour. In reality, it requires a thorough stirring and is time-consuming

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24 | production

Realize the problem, solve the problem

Emulsifying in a batch process Claus-Wilhelm Häbel Michał Kaczmarek

In the Chemical Industry as well as in the Pharmaceutical and Cosmetics Industry, emulsifying in a batch process is a significant processing step. Problems in the production will follow if the incorrect or inappropriate mixing equipment is selected.

Emulsions are based on liquids that under normal conditions are not

Main effect of the coating of the droplets is the repulsion of the

easy to be mixed together to a homogeneous mixture. The physical basis

droplets to each other inside the surrounding continuous phase.

for this behaviour on one hand is the different density, and on the other

A separation of the disperse phase and recombination of the droplets

hand the electro-chemical properties of the liquids involved. Only when

is not possible anymore.

using mechanical energy in form of shear energy and an emulsifier, it is

The energy applied in this phase is very low, and not sufficient for

possible to homogeneously combine two or more immiscible liquids to

the emulsifier to inhibit larger droplets from coalescing. Processing aim

an inseparable mixture, a stable emulsion.

is to produce a large number of very small droplets with the respective

Processing of emulsions basically is a two step production,

large surface.

a mechanical part and a electrochemical part. In the mechanical part, the disperse phase is dispersed to very small droplets. This is executed

Normal stirring systems won’t suffice

with shear energy that is applied to the mixture. Without the adding of an

Generally during an emulsifying process, a pre-emulsion is produced

emulsifier, these small droplets immediately would recombine, constantly

in a batch and then additional „emulsifying” or „homogenising” is applied.

increase its size and soon float as a separated large bubble in the vessel.

The preemulsion is already the ready made mixture of a continuous and

The electro-chemical part is used to bring the emulsifier as quick as

a dispers phase and the added emulsifier. To get the required droplet

possible and in dosed quantities in contact with the small droplets.

size, simple standard or conventional stirrers are used that are not able

The aim of this step is to coat the surface of the dispersed droplets

because of the low shear energy to produce small droplets. Conventional

with the respective amount of emulsifier to change the electrical load of

stirrers in many cases are oriented radially and not axially and there

the so-called „Micell” to avoid the attraction of other „Micells”.

is an uneven mix of the two phases from top to bottom of the vessel

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25

combined with increasing or decreasing droplet size towards the surface of the mixture. Because of the rotation of the liquid in the vessel, like in a centrifuge, large particles are accelerated to the outside of the vessel while light particles remain at the inside.

It is obvious that such a pre-emulsion will result in an unsatisfactory additional emulsifying process. Further processing steps and machines, such as Inline dispersing machines that are continuously supplied with product from the outlet of the vessel have to treat continuously changing concentrations and droplet sizes.

Mandatory for a homogeneous and reproducible batch emulsifying process is a perfect mixing of the contents in the vessel in combination

a homogeneous pre-emulsion is fed to the additional processing step.

with a system that applies sufficient shear energy to delay the dispersed

The Dispermix replaces the very often used combination of a batch

droplets from recombining until the emulsifier has coated their surface.

dispersing machine and stirrer and this results in lower purchasing

The Dispermix system offers especially for emulsifying in a batch

cost and simple processing controls. The system may be used in low to

or the production of a pre-emulsion many advantages compared to other

medium viscosity products without any additional form of mixer. Where

conventional systems. The basis of the system is the Jetstream mixer

high viscosity products have to be treated, then the dispersing mixer may

with a rotor-stator system combined with a batch shear ring machine.

be combined with a wall scraper that feeds the product directly into the

The design of the head is equal to the Jetstream mixing head that uses

dispersing and mixing head.

most of the applied energy to create a vertical flow of the liquid in the

As well as the emulsifier, very often stabilisers are used to adjust the

vessel different to other stirring or mixing principles. Additionally the

„mouth feeling” characteristics of products in the food industry. These

Dispermix mixer creates the maximum speed in its centre and not at the

products also interact with the electrochemical effect as they form a kind

edges of the blade and such absolutely suspends any sedimentation in

of ion layer around the particle resp. droplet and reduce the immobility

the bottom of the tank and it also increases the heat transfer with the wall

of the complex mixture due to its size and load. In extreme cases, the

of the tank. The slots in this head and the defined radial gap (distance of

system comes to a complete standstill. Stabilisers in many cases are

the rotor from the head) provide much higher shear energy compared to

supplied in powder form, and a loss of powder can be suffered during

the normal Jetstream mixer or other stirring elements.

addition into the liquid. Many of these powders become sticky when they

The shear gradient (quotient out of peripheral speed of the rotor

come in contact with a liquid and these stick to the wall or the mixing

and gap) in this case is much larger, and this again results in a smaller

shaft in the form of big lumps or crusts. As a result, filter systems are

droplet spectrum. The emulsifier can be added directly into the head of

required to remove these impurities.

the emulsifying system and thus to the area where the small droplets are

The problem when adding such powders is that after adding it to

created. This ensures that the coalescence is as short as possible and

the surface a large quantity of agglomerated lumps are formed that,

most of the small droplets are immediately coated with the emulsifyer.

compared to the liquid, have a lower density and for this reason float on

In many cases an additional processing step with an inline dispersing

the surface (CMC, Xanthan, Pectin, etc...). With radial acting stirrers it

system is no longer required as the quality of the emulsion after this step

is very difficult to force these agglomerates and lumps from the surface

is already satisfactory.

into the liquid, and long treatment time is the result. In such cases these stirrers are operated in highest speed to achieve a Vortex to draw the

Mixing effect similar to a Jetstream mixer

powder into the liquid, but this also incorporates unwanted air as well.

With this type of dispersing system the whole contents of the vessel

This air causes oxidation and such an uncontrollable change in the

is homogeneously mixed. From start to the end of the pre-emulsifying

quality. The Dispermix does not cause a Vortex and as such eliminates

process, it is guaranteed even during emptying of the vessel that

the problems described above.

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26 | production

How to optimize efficiently?

New process optimization method Paweł Kitzman

Optimization has been applied in many industrial branches.

It serves the improvement current processes as well to create new ones.

Its competent application brings possibility of obtaining maximal quality accompanied with minimal cost.

There are various definition of a process. Under standard

indication real optimum. In activity of that type the following simple cal-

PN-EN ISO 9 0 0 0:20 0 0, p.3.4.1 (Q ualit y Managing System.

culation is not taken into account. If we have in our process 10 variables

Basis and Nomenclature) we call the process a set of mutu-

and we accept approximate operation, that every variable is accepted

ally related or mutually influencing operations, which trans-

in gradation to three levels in order to cover whole variability space

form inputs to outputs. According to Bussines Dictionary.com

(agreeing of course to imprecise cover), we must produce 103=1000

(http://www.bussinessdictionary.com/definition/process.html), process

prototype variants. Such high number of variants nobody produces of

is a sequence of dependent and connected procedures, where on every

course. More realistic number is rather closer to 10 than 1000, so stating

stage one or many resources (employers’ time, energy, machines,

that we deal with optimization is abused.

money) is of use, to convert inputs (data, materials, parts) to outputs.

Overall speaking, optimization problems we can split to that type

These outputs make inputs to the next stages, up to gaining aim or

where we understand the essence and we can describe the system with

final result.

“á priori” equations, and to such problems, where we can’t describe by

First definition will surely address to persons intensively using

equations. The second type of problems prevails in biology, medicine

computer in their work, the second is preferably addressed to industry

and pharmacy. As to the latest group of problems, if great amount of

representatives, whose realm are tangible activities. I would like to

experimental variants could be performed, we could describe it with

stress that both definitions do not refer to any substantial processes,

“á posteriori” equations. It is unrealistic in practice with regard to cost

so they are abstract, and this is normal because if we talk about

and time, on the whole. In problems that could not be described with

optimization of the processes, we especially bear in mind mathematical

equations there is possibility to optimize in spite, for instance with

methods, enabling highest precision and effectiveness in calculation

step by method.

optimum, and mathematics is an abstractive discipline. Mathematical methods just due to their abstractness can be applied in various,

Details of the new method

frequently unrelated disciplines. With this feature of mathematical

Elaborated method, relying on application special neural

methods, the second important property, generally obscure to average

network and special pre-processing accompanied with the step

user relying on fact that quality and usefulness does not prove to be

by step method has the following features distinguishing it from

an application in one certain discipline. It frequently happens that

other known methods:

industrial employees put questions in a form: if the method turns out to

•

Special neural model can be based on a few amount of experimental

be successful in discipline X it means it is successful in discipline Y. In

cases (if we imagine “common” activity aiming at optimization,

fact, for the user of mathematic method more important question is: with

it means for instance 10 control variables in process, and having

what standard data base the method was tested. Due to introduction

regard previous experience, we can base on twenty or a little more

base test data it is possible to compare methods and with practical

experiments, preserving continuous character of variables).

point of view it should be stated that some methods give better results

•

in classification problems and the other in regressive ones.

important errors that could have been detected even performed

In Poland unfair belief prevails that optimization is an activity relying on an evaluation of certain amount of prototype production variants and

Due to special pre-processing, cases burdened with significantly only once.

•

The method is useful for finding subliminal influences giving

choosing one of them as the best. That type of activity refers to various

synergistic effects; therefore, we can realize new groups of drugs

disciplines (not only to pharmaceutical industry) and does not serve

basing on above mentioned principle.

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27 •

Described method gives the possibility of simultaneous optimization

to indicate experimental cases burdened with significantly important

of mixture contents and/or concomitant processes.

errors. These cases should be eliminated or repeated.

Essential stages of the described optimization method presents the following schedule.

The farther procedure is to create basic neural model (working model), that could be used to optimization process according to step by step method by Nelder-Mead1 algorithm. The latest algorithm, if applied separately as stand alone method h a s d i s a d va nt a g e th at e a c h n ex t s te p re l y in g o n simplex transformation long the hyper-surface must be preceded by obtaining results from the previous step, so it is algorithm which in practice makes significant prolongation.

A little bit of mathematics N-dimensional simplex in n-dimensional linear space we call the smallest set of points creating figure (convex set) of n+1 vertexes. Each vertex in simplex has coordinates that are all control variables and output variable in the form of integrated target function.

Response hyper-surface is a surface connecting all points of integrated target function that must be defined before starting optimization project. Defining integrated target function we must first define individual target functions characterizing respective output variables.

In maximization for i-ed output variable (i-ed target in optimization project) we define target function in the following Performing optimization project we should set our sights on

manner:

particular aims. We can distinguish three kinds of aims: •

minimization of output variable,

•

maximization of output variable,

•

gaining the target value of output variable (certain, pre-set value).

The latest kind of aims is particularly important in the case of generic

ě0, Yˆi Ł Ymin ď R ďďé Yˆ - Y ů m( yi ) = íę i min ú , Ymin < Yˆi < Ymax ďëYmax - Ymin ű ď ˆ ďî1, Yi ł Ymax

drugs, because parameters of final products should be identical with

where:

original products.

Ymin – is lower limit of acceptability for value Yi

Of course, we can have several aims in optimization project – the number equivalent to number of variables.

Ymax – is a value, above which farther increase is meaningless R

– is a factor, that may receive various values (0,1 to 10 in practice)

Next we should plan experiments. Statistical method “Central

We have more than 3 variables in optimization model as usual,

Composite Design” (being certain kind of optimization the number of

that’s why space, we are talking about, is multi dimensional and rather

experimental variants) is applied as usual. It has many modifications,

impossible to realize. The surface, we are talking about, is not flat

for instance for sets of conjugated variables (in mixtures we have

(two-dimensional), but has much more number of dimensions. If we

conjunction, because components must complete to 100%) and sets

have long-lasting processes, the time length of completion of whole

of independent variables (as it takes place in the case of physically-

the project only on the base of Nelder-Mead algorithm could not be

-chemical technological processes). When we have experimental plan,

acceptable.

it is worth while to verify it with regard to “historical” data, if such data exists. If we find in “historical” data variants close to planned variants, we can diminish cost of experiments.

If we have got minimization as a target, then we use reciprocal of maximization function.

If we have on the other hand target value to obtain, thus bigger or

Next stage consists of application of special neural network and

smaller values are unacceptable and we aim at obtaining one pre-set

special pre-processing, relying on intentional addition a noise to data

value. That kind of aim is frequently related with guideline standard

and preliminary neural model is created. This model serves mainly

value. Then, it is a target imposed by regulation.

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28 | production

Definition of target function relying on obtaining given value (target

Integrated target function has a form of weighed geometric mean: 1

value) presents as follow:

b M ( y ) = [m( y1 ) ´ m( y2 ) ... ´ m( yi ) ] ĺ i b1

ěéYˆ - Y ů R ďę i min ú , Ymin < Yˆi Ł Ci ďëCi - Ymin ű ď R ď Yˆ - Ymax ů m( yi ) = íé ę ú , Ci < Yˆi < Ymax ďëCi - Ymax ű ď ď ď0, Yˆ Ł Y lub Yˆ ł Y min i max î i

bi

b2

where: M(y) – is an integrated value of target function M(yi) – is a target function for individual output variable βi

– is a factor of share of individual output variable in integrated target function i is a number of output variables Magnitude of factor βi in the scopes 0 ≤ βi ≤ 1 we can chose for

where:

each output variable individually, dependently on our preferences. The

Ymin – is a lower limit of acceptability of value Yi

closer the factor βi is to value 1, the sooner we get our target (desirable

Ymax – is an upper limit of acceptability of value Yi

value for output variable) and will be stronger expressed in relation

Ci

– is a factor, that can receive various values

to other variables.

Above presented functions define targets we are aiming at in overall way. In practice, performing successive steps of transformations con-

In the figure 1 various shapes of target function with various values

secutive simplexes we use rules and application of them is equivalent to

of R factor for maximization problem are presented and in figure 2 for

obtaining aims expressed by above functions. This set of rules is being

obtaining target values.

presented below as an example of simplex transformation.

Let’s imagine very simple technological process, where quality of final product is defined by only one output variable, which depends only on two control variables X1 and X2. In that case simplex is a triangle, because simplex has k+1 vertexes, where k is the number of

1 0.9

control variables. This is a true statement, when we deal with not con-

R=0.1

0.8

jugated control variables. If we have conjugated control variables (like

0.7

R=0.3

0.6

in a mixture), the number of vertexes in a simplex equals k.

0.5

Transformations of simplex during performing optimization

R=1

0.4

project in industry concerns figures with greater amounts of vertexes

R=3

0.3

R=10

0.2

than tree. After all number of output variables is greater than one.

Space where simplex is transformed has number of dimensions

0.1 0

Y max

0Y min

Fig. 1. Shapes of integrated target function for maximization problem, with various values for R factor. Conventional scales are on the axes

equal to the sum of all control variables augmented with one (for integrated target function). For three control variables simplex is a tetrahedron, for greater number of control variables simplex is a hyperhedron of higher order and it is difficult to imagine in space because we are familiar with real three dimensional world. That is why farther reasoning about transformations of simplex I limit only to three dimensions in propose of simplification.

1 0.9

If we have only two control variables then simplex is a triangle, that R=0.1

0.8

we can transform according to figure 3.

R=0.3

0.7 0.6

This is a principle of the so called modified simplex, where the following transformations are possible: negative contraction, positive

R=1

0.5 0.4

contraction, reflection and expansion. Transformation form can be

R=3

0.3

selected accordingly hyper-surface slope. If the surface has raised

0.2

suitably steep from several latest transformations of the simplex,

0.1

we can allow for expansion, it means kind of transformation which

0 0Y min

Y max

Fig. 2. Shapes of integrated target function for obtaining target value problem, with various values of R factor. Conventional scales are on the axes

1/2012

in the fastest way leads to the target. Dependently of the degree of “profitability” of making moves aiming at maximum, also other possible kinds of transformations are chosen. An application which is only mere reflection during whole project stands for classical method.

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production | 29

The following example performed in optimization project of the second stage of synthesis of propranolol can prove the effectiveness of the method.

Process of synthesis All in the above project were 8 variables. Project was performed on the base of only 10 experimental variants. Optimization targets were: • maximization of reaction yield, • achievement of target melting temperature, • cost minimization.

• (Significance of performed project was only educational-demonstrative, because propranolol (substance) in Poland could be cheaply imported from India.)

O O

C C H2 H

CH2

O H2NCH(CH3)2

H C C C N H2 H H OH 2

CH3 CH CH3

1-(α-naftoxy)-2,3-epoxypropan + izopropylamine → → R,S-1-izopropylamine-3-(α-naftoxy)-propan-2-ol

The following results were obtained: • reaction yield was enlarged by 20,87%, • cost of process was diminished by 65,88%, • desired melting temperature of final process was achieved, that differed from “handbook” value by only 0,29%.

Control variables:

Output variables:

1. Volume of toluene

1. Reaction yield in relation to epoxypropan 2. Melting temperature of propranolol 3. Cost of the process

2. Time of heating 3. Time of prolonged condensation 4. Volume of acetate-ethylate during crystallization

5. Volume of acetate-ethylate during rinsing

to application special neural modeling it is possible to optimize basing on few number of samples (experimental variants). Moreover the possibility arises in order to find out experiments which were performed badly, even if they were not repeated.

Above paper was written not going deeply in particular matter and not focusing on examples, because process optimization due to its mathematical abstractness approach can find various applications.

It refers especially to above presented method, which positively distinguish amongst other known methods in small requirements as to the number of necessary experiments to execute and in credibility with regard to algorithm allowing for detection “defective” experiments.

What I would like to conclude with is an encouragement directed towards a reader to find practical application of the given method; however, exceptionally not in technological processes and possible cooperation with an author. Phone: +48 609 511 508, e-mail: pawel.kitzman@wp.pl Fig. 3. Four possible transformations of one of vertexes in a simplex

Simplex is a triangle WBN. Placement of vertex W is subjected to

References • •

transformations. There are the following possibilities: •

C w – negative contraction CR – positive contraction R

– reflection

E

– expansion

•

Conventional scales are on the axes The essential feature of new optimization method is composition of special kind of neural modeling and Nelder-Mead method. Thanks

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

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•

1)

Nakai S. (1981) – Comparison of Optimization Techniques for Application to Food Product and Process Development – J. Food Sci. 47, 144 – 152, 176.

Nakai, S.; Koide, K.; Eugster, K. (1984) - A new mapping super-simplex optimization for food product and process development. - J. Food Sci. 49, 1143-1148, 1170.

Walters F.H., Morgan S.L., Parker J.R., Deming S.N. (1991) – Sequential simplex optimization: A technique for improving quality and productivity in research, development, and manufacturing – Boca Raton CRC Press.

Internet Podręcznik Statystyki. Sieci neuronowe. Stat Soft Electronic Statistics Textbook. Copyright: StatSoft Inc. 1984 – 2010. (http://www.statsoft.pl/textbook/stathome_stat.html?http%3A%2F%2Fwww. statsoft.pl%2Ftextbook%2Fstneunet.html) J.A. Nelder and R. Mead: 1965. A simplex metod for function minimization.

Komputer Journal, vol 7, pp 308-313

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30 | production

Impurities in generic drug substances and products Dr. Christian Zeine LGC Standards

Impurities are always present in drug substances and products in trace quantities.

Limit and threshold values are specified by official bodies and legislation such as pharmacopoeias and ICH guidelines. A closer look into European and US American legislation reveals that for generic pharmaceutical articles also ICH principles needs to be applied. That means it is not enough to just show compliances to the monographs of the European Pharmacopoeia (Ph.Eur.) or the USP (United States Pharmacopeia), but also to check the impurity profiles in much more details.

Dedicated reference standards for impurities can help in the development

APIs and medicines thereof, there is now legislation out in Europe and

and validation of analytical methods for impurity control, and are also used

USA stating that the principles of ICH Q3A and Q3B needs to applied to

in the routine analysis of drug products. The smart use of these materials

generic APIs and products of those. The principles are discussed in further

can avoid extensive qualification studies. It is also important to chose the

detail in the next chapters.

right materials in order to avoid hidden costs.

This article is in wide parts a translation of the original article “Verunreinigungen in generischen Arzneimitteln” by Dr. Christian Zeine, published in German language in “pharmind – Die pharmazeutische Industrie” in volume 8, 2011.

Inorganic Impurities Inorganic reagents are required for the production of the API. Phosphates, for example, are commonly used as buffers during the reaction to adjust the pH, and organometallics are often used as catalysts in reaction

Types of impurities, background According to the International Conference on Harmonization (ICH),

processes. Inorganic molecules count as impurities and have to be removed as far as possible from the end product.

impurities are defined as substances in the active pharmaceutical ingredient

Inorganic impurities are also dealt with in [1] and [2], but only very general

(API) that are not the API itself [1]. For a pharmaceutical formulation (that is, a

and with this reference to pharmacopoeias and other scientific information

tablet or suppository), impurities are defined as substances in the product that

for suitable and sound limits. A guideline Q3D on metal impurities is

are not the active pharmaceutical ingredient (API) itself, nor the excipient used

currently in preparation, but in very early phase yet. Further information on

to manufacture the relevant pharmaceutical [2]. Investigations for their presence

the development of Q3D can be found on the ICH website (www.ich.org).

or absence are important due to their risk potential. Impurities can themselves

Inorganic impurities will not be discussed any further in this article.

be pharmacologically or toxicologically active and they can also reinforce or diminish the pharmacological efficacy of the API. Sometimes impurities may even be teratogenic, mutagenic or carcinogenic. Impurities can be divided into three categories: organic impurities, inorganic impurities and solvents.

Residual solvents The manufacture and work up of APIs generally occurs in the liquid phase. Because of the nature of most APIs, water is often not a suitable solvent, and organic solvents – which are often toxic – can be necessary.

Organic Impurities

Specified concentrations of such solvents should not be exceeded in

These arise during production and/or storage of the API and can be

the end product. The potential toxicity of the solvent and the technical

starting materials, by-products or degradation products. Organic starting

feasibility of removing it from the API have to be considered as part of the

materials and by-products are removed as much as possible after the

specification process.

production through downstream processing of the API. Degradation products, however, cannot be removed from the finished product. Stability

The ICH Guideline Q3C in its fifth revision [3] deals with residual solvents.

Residual solvents will not be discussed any further in this article as well.

tests must be carried out to prove that such degradation products do not exceed certain limits during the product shelf-life. Those limits must

Impurities in generic products – Europe

have been previously defined and justified for each degradation product.

As mentioned above, the present European legislation states explicitly

The ICH Guidelines Q3A [1] and Q3B [2] – both in their second

that ICH guidelines need to be applied to generic products as well, and

revisions – deal with organic impurities. Originally developed for new

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that it is not enough to test according to the monograph only.

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31 The central document here is the directive 2001/83/EC [4] , where it is said:

Furthermore, the EMA appeals to Ph.Eur. to continue the revision

“However, where a material ... has been prepared by a method liable

process for ‘old’ monographs and to identify – in cooperation with the

to leave impurities not controlled in the pharmacopoeia monograph, these

other responsible institutions – those monographs that need to be revised

impurities and their maximum tolerance limits must be declared and a

most urgently: “…European Pharmacopoeia to continue its current revision

suitable test procedure must be described.”

programme (maybe it should be identified together with the authorities which

Most European Pharmacopoeia (Ph.Eur.) monographs were developed

active substances have priority, and/or the QWP might also like to identify

on the basis of documentation from the original producer, and include only

active substances for which a revision of the old monograph is not considered

impurities known from those synthetic pathways. However, once generic

necessary).”

versions of an API are produced, new impurities from different synthetic

Based on this, numerous monographs were updated in the last years

pathways might occur. These impurities might not be under sufficient

by replacing thin layer chromatography with HPLC methods and applying

control by the current Ph.Eur. monograph, hence needs to be monitored

limits on impurities which are in accordance with the ICH guideline Q3A.

by additional measures and measurements.

Since [5] is in force, the EDQM has denied validity status to approx.

Additionally, there is a number of so called ‘old’ monographs existent

30 CEPs during their renewal processes, nine of those in 2011 [12, 13].

in the Ph.Eur. in which the testing on impurities is still managed by thin

Most of the owners for these CEPs are from China and India. For a lot

layer chromatography with a general acceptance limit of £0.5%. These

more CEPs, the valid status was suspended. Additonally, numerous drug

old monographs do not reflect at all recent developments (e.g. newer

substances manufacturer have not applied for a renewal of their CEPs,

chromatographic techniques) and findings.

or have withdrawn the CEP on their own. The updating of the Ph.Eur.

These two facts are addressed in European legislation since April

monographs is the most relevant cause for this development.

2004, when the European Medicines Agency (EMA) published its “Guideline on Control of Impurities in Pharmacopoeial Substances” (CPMP/

Impurities in generic products – USA

QWP/1529/04) [5]. This guideline refers to two very important texts of the

Comparable with the EU directive [4], the Code of Federal Regulations

Ph.Eur.: The general monograph “Substances for pharmaceutical use” [6]

Title 21 requires under paragraph 314.94 (a)(9) to test on ‘inactive

and the general text “Control of impurities in substances for pharmaceutical

compounds’ (meaning also impurities, the author) [10].

Comparable with the EMA guideline [5], in June 2009 and November

use” [7]. These two texts link the requirements of each single Ph.Eur. monograph with the requirements of the guideline Q3A of ICH.

2010 the FDA issued two guidances for industry “ANDAs: Impurities in drug

The EMA states in [5], that a lot of ‘old’ monographs do not satisfy

substances/products” [8, 9]. There, the FDA states very clearly that the

the requirements of [6] and [7]. Therefore marketing authorisation for a

principles of ICH guidelines Q3A and Q3B need to be applied to generic

certain product should not be granted when submitted CEPs (Certificates

articles as well. However, unlike EMA the FDA refers directly to the ICH

of Suitability) or EDMFs (European Drug Master Files) refers to such an

guidelines and not to certain texts in the United States Pharmacopeia

‘old’ monograph only:

(USP), as such texts are not existent in USP at present:

“Every time an application for MA is made by a pharmaceutical

“The Q3B(R) was developed by the International Conference on

manufacturer for a medicinal product containing a pharmacopoeial active

Harmonisation (ICH) to provide guidance on impurities in drug products

substance, the reference member state should check, when reference to

for new drug applications (NDAs). However, the Agency believes that

a monograph is made (e.g. CEP, EDMF), that this monographs complies

many of the recommendations provided on impurities in drug products

with (1) and (2) [here [6] and [7], the author] above. If not, the applicant

also apply to ANDAs.” [9] The FDA guidances are dealt with in more detail in the next chapter.

should be requested to propose a revised specification in line with (1) and (2), before an authorisation is granted.”

Also, in [5] the EMA appeals to the EDQM (European Directorate for the

The FDA guidances on impurities in generics

Quality of Medicines, responsible for granting CEPs and for publishing the

According to the FDA guidances, a dossier for an ANDA should contain a

Ph.Eur.) not to grant or renew CEPs which are based on ‘old’ monographs:

list of impurities. What organic impurities is concerned, that list should include:

“A certificate [CEP, the author] should not be granted if based on an „old”

•

Each specified identified impurity/degradation product

monograph i.e. not complying with (1) or (2) [here [6] and [7], the author].

•

Each specified unidentified impurity/degradation product

The applicant needs to make a new proposal to obtain the certificate; this

•

Any unspecified impurity/degradation product with an acceptance criterion of not more than (≤) the identification threshold of the respective

would then serve as the basis for the revised monograph.

ICH guideline (see table 1 for exemplary thresholds from Q3A)

In the case where a CEP has been granted, based on an „old” monograph, a revision should be initiated during renewal of the CEP.”

•

Total impurities

Maximum Daily Dose 1

Reporting Threshold 2,3

Identification Threshold 3

Qualification Threshold 3

≤ 2g/day

0,05%

0,10% or 1,0 mg per day intake (whichever is lower)

0,15% or 1,0 mg per day intake (whichever is lower)

> 2g/day

0,03%

0,05%

0,05%

Table 1. Thresholds for reporting, identification and qualification (from ICH-Guideline Q3A(R2) – Impurities in New Drug Substances)

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32 | production For the setting of specifications, the FDA guidances contain decision

the worst case, qualification means toxicity studies on animals which

trees which are comparable to those from the respective ICH guidelines.

are expensive and time intensive, and can delay the time-to-market

The FDA also states that for impurities specified in a USP monograph,

easily for 4-5 months.

that USP specification should be applied. If USP specification can not

Figure 1 shows the decision tree from [8], with extentions from the

be kept, then the impurity needs to go through a qualification procedure.

author reflecting a possible USP specification. Two critical positions

In this context, qualification is the process of acquiring and

(exclamation marks!) need to be pointed out.

evaluating data that establish the biological safety of an individual

Firstly, it is most desirable to answer the question “Reduce to not

impurity or a given impurity profile at the level(s) being considered. In

more than qualification threshold?” with “Yes”. This is because to

Fig. 1.

Decision tree of FDA guidance [8]. Grey fields and arrows starting from there are not part of the original decision tree. The exclamation marks are set by the author, and mark critical positions in the tree, which are addressed in the text.

1/2012

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production | 33

answer with “No” would mean to enter into the qualification procedures

•• not releasing batches which are ok,

mentioned above. However, to reduce an impurity physically in the

•• undervalued stability, thus too short shelf lifes,

product (e.g. by purification processes, change of synthesis routes

•• and finally unnecessarily initiated qualification studies according

or change of supplier of active pharmaceutical ingredient) will always

to ICH.

mean a laborious process which is very time consuming and expensive as well.

Occuring of such events normally means manifold higher costs than

The same applies – secondly – when there is the obligation to reduce the considered compound to a safe level.

those that would have been raised by using a completely characterised impurity reference standard right from the start.

Before entering into one of the processes to reduce a certain

Well characterised impurity materials are also of high value in the

impurity to a certain amount physically, one should be absolutely sure

development and validation of analytical methods. The ICH guideline

– by a real quantitative determination of the impurity in question – that

Q2(R1) [11] suggests the use of such materials whenever available,

it is indeed present above qualification threshold or above the safe

for validation of

level. Because up to this point, the impurity content very often is only

•• specificity of assay and impurity tests

estimated roughly by assuming the same analytical response of drug

•• and accuracy of quantitative impurity tests.

substance and impurity. An accurate determination of the impurity is possible with a dedicated reference standard for that impurity. The

Literature

positive effect can be that in fact the compound is below a safe level or

[1] ICH Guideline Q3A(R2) – Impurities in New Drug Substances;

qualification threshold, without the further need to reduce it physically in the pharmaceutical product.

Also the correct establishing and checking of relative response factors should be done with such dedicated impurity reference standards.

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q3A_R2/Step 4/Q3A_R2__Guideline.pdf [2] ICH Guideline Q3B(R2) – Impurities in New Drug Products; http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q3B_R2/Step 4/Q3B_R2__Guideline.pdf

Reference standards for impurities The Ph.Eur. and USP offer a range of reference standards for impurities. However, those are designed solely for the pharmacopoeial

[3] ICH Guideline Q3C(R5) – Impurities: Guideline for Residual Solvents; http://www.ich.org/fileadmin/Public_Web_Site/ ICH_Products/Guidelines/Quality/Q3C/Step4/Q 3C_R5_Step4.pdf

purposes described in the compendial books, and not very useful

[4] Directive 2001/83/EU from 6 November 2001 p. L 311/105

for any other purposes. For example, a lot of those materials are

http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_

only used qualitatively. The quantitative use of those substances (by

cons2009/2001_83_cons2009_en.pdf

using a default assay value of 100%) then normally means to grossly

[5] EMA Guideline CPMP/QWP/1529/04; Guideline on Control of

overestimate levels of impurities in own products. Furthermore, mono-

Impurities of Pharmacopoeial Substances, 2004 www.ema.

graphs might change, and so the supply with certain impurities from the pharmacopoeiaas might change as well. A sustainable availability is not secure at all.

europa.eu/pdfs/human/qwp/152904en.pdf [6] European Pharmacopoeia 7.0, Vol. 1 (English version), General monograph (2034), S. 694 ff.

A most reliable supply is given by commercial vendors. However, it is important not to confuse reference standards with just fine chemicals

[7] European Pharmacopoeia 7.0, Vol. 1 (English version), General text 5.10., S. 631 ff.

here. Also the extent of analytical information can vary considerably

[8] FDA Guidance for Industry; ANDAs: Impurities in drug substances,

between different suppliers of impurity reference standards. The

2009 http://www.fda.gov/downloads/Drugs/GuidanceCompliance-

certificate of analysis (CofA) accompanying the material should at least

RegulatoryInformation/Guidances/UCM172002.pdf

comprise an identity method (e.g. NMR), a purity profile per HPLC and water and residual solvents determination. From HPLC purity, water and residual solvent results an assay value of the impurity reference standard is then calculated on the CofA. However, many suppliers just provide a ‘chromatographic purity’

[9] FDA Guidance for Industry; ANDAs: Impurities in drug products, 2010 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u cm072861.pdf [10] 21 CFR 314.94(a)(9)

http://www.accessdata.fda.gov/scripts/

cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.94

on their CofAs, to be able to offer a cheap material. Depending on

[11] ICH Guideline Q2(R1) ht tp://w w w.ich.org /fileadmin/Pu-

the quality of the chromatographic method (which might be just thin

blic_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/

layer chromatography), and depending on the undetected amounts of

Step4/Q2_R1__Guideline.pdf

water and residual solvents in the ‘reference standard’, the ‘true’ assay value can then be grossly overestimated. This will lead in turn to an

[12] CEP databse of EDQM https://extranet.edqm.eu/publications/ Recherches_CEP.shtml

overestimation of the impurity in the pharmaceutical product. The use of

[13] Certification of suitability to Monographs of the European

such a cheap material might then result in further hidden costs through

Pharmacopoeia, MONTHLY REPORT PUBLICATION March 2011

•• unnecessary OOS results,

http://www.edqm.eu/medias/fichiers/March_2011.pdf

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34 | production

Quality Packaging Solutions for the pharmaceutical industry Hanna MoczyĹ&#x201E;ska Area Sales Manager Pharmaceutical Packaging Eastern Europe SCHOTT POLAND Sp z o.o.

Drug stability and safety of the growing segment of highly sensitive new drugs put special demands on the packaging. However, these topics have also become a primary focus of the pharmaceutical industry in general, among others driven by the trends in regulatory requirements for drug containers and an increased focus of the US Food and Drug Administration (FDA) on glass quality issues.

Material expertise and specialized analytics

pharmaceutical ingredient shows a higher chemical stability and a longer

Experts in the development and processing of specialty glass use pre-

shelf life. It also reduces the adsorption of proteins and diagnostic agents.

mium quality borosilicate glass tubes. The very well controlled manufacturing

Biotech components are very effective but also cost intensive and highly

process of these tubes shows superior stability and reliability in the converting

sensitive. To preserve such products for a longer period of time, keeping their

process. During the converting of glass tubes to drug containers, factors

effectiveness stable and better protecting the highly effective and sensitive

contributing to a stable inner surface of the container include temperature

ingredients, pharmaceutical companies often use lyophilization (freeze-drying).

and time of heat exposition during glass conversion. Control of these critical

However, the lyophilization process puts special demands on the packaging.

process parameters is key for pharmaceutical applications. Tools and

The ultra-thin hydrophobic interior coating and the special geometry of

procedures to control these parameters and to optimize the chemical stability

packaging prevents freeze-dried ingredients from adhering to the wall of a

of the containers nowadays itâ&#x20AC;&#x2122;s a must.

container and minimizes glass breakage.

Another new coated packaging solution addresses the costly overfill

Resistant to delamination

practice of pharmaceutical companies to compensate the loss that is caused

Delamination is a dissolution of the glassy network which can be

by adsorption of drugs on the container surface. This coated vial minimizes

caused by alkaline attacks, for example, and leads locally to a full reduction

the residual volume of liquid drugs through a special coating which leads to

of chemical bonds. In combination with mechanical impact or chemical

reduced costs for the pharmaceutical company.

interaction with the drug, this can lead to the formation of tiny glass particles or lamellae in the drug.

For the special needs of highly sensitive drugs, there is a solution of innovative staked needle glass syringe that is designed in such way that the

Recent market recalls for injectable drug products due to visible flaky

drug does not come into contact with neither the metal of the needle nor the

particles have put the topic of glass delamination into the focus of the industry.

glue during storage. Such a new sterile syringe system does not allow the

Primary packaging experts offers different high-quality alternatives to

active ingredient to flow into the needle until after the syringe has been opened

conventional primary pharmaceutical glass packaging,

by removing the needle shield. This prevents drugs from interacting with the

In order to avoid the risk of glass particles, pharmaceutical companies

adhesive or the metal of the needle and thus improves storage and the stability

can switch to products which are made of high-tech COC polymer. It is also

of highly sensitive injectable drugs. In addition, the system allows for extremely

possible to benefit from the advantages of glass and at the same time being

thin needles that help reduce the pain caused by injections.

protected against glass particles with vials featuring a coating layer that protects the formulation and the glass surface at the same time.

Ready-to-fill, made of COC polymer syringe systems with low extractables, and without ions and heavy metals, reduce the drug container interaction. They are break resistant, light weight, and transparent with a glass-like appearance.

Innovative packaging solutions for new drugs Complex and highly sensitive biopharmaceuticals are increasingly gaining

The high moisture barrier of COC high-tech polymer enables the long-term storage of drugs even in small containers.

in importance and thus require innovative packaging solutions. Packaging

Quality is everything to pharmaceutical companies. Advanced technologies,

solutions with high-tech barrier layers to improve the stability and shelf life

modern manufacturing plants and carefully trained and qualified employees

of these sensitive active ingredients are available on the market for example

are therefore a must for manufacturers of pharmaceutical packaging in order

vials with a quartz-like coating that creates a chemically completely homo-

to consistently meet the worldâ&#x20AC;&#x2122;s highest standards for quality and meet the

geneous container surface and better barrier properties so that the active

requirements of international pharmacopeia.

1/2012

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Trigger

production | 35

happy

James Tucker

Portfolio Manager, Sterile Environmental Hygiene EMEA, Shield Medicare Ltd

Neil Simpson

R&D Project Manager, Shield Medicare Ltd

Steve Moss

Technical Service Manager, Facility Monitoring System (part of the Validair Group)

Trigger sprays are a convenient way to dispense disinfectants but not all sprays are the same. James Tucker1, Neil Simpson2 and Steve Moss3 outline a study used to show that some trigger systems are affected by suck-back.

The new SteriShield Delivery System safeguards the continued sterility of

Study protocol

the contents of trigger spray bottles by eliminating the risks associated with

The development of the new trigger led to an investigation into

â&#x20AC;&#x161;suck- backâ&#x20AC;?. In a conventional trigger spray suck- back allows potentially

whether there were more stringent ways of validating it than the media

contaminated air into the bottle, which can in turn contaminate the liquid inside.

test alone. The two standard ways of monitoring contamination in a

Since its introduction, the system has been widely used to protect successfully

cleanroom are by particle counts and by media tests. It was therefore

the integrity of sterile alcohols, biocides and neutral detergents in trigger spray

decided to include particle counts as part of the validation.

presentations for pharmaceutical applications.

The objective of the test was to ascertain what is actually happening to

A validation study was designed to explore the potential risk of contamination being brought into a system via the only possible point of entry, the trigger

the air within the bag while it is in use, i.e. does any outside air get drawn in, thereby creating a potential chance of contamination?

head. The study compared the number of 0.5pm and 5pm particles drawn

It is not possible to place a particle counter inside the bag to check for

into various trigger systems, including the SteriShield Delivery System trigger,

airborne contamination but it is possible to create a sealed test system for the

during use to present a quantified assessment of the risks from suck-back.

trigger spray head by sealing it onto a special test bottle. The air from inside

The new trigger system has two main component parts: the bottle with

the special test bottle can then be passed through a remote particle counter,

a co- extruded integral Surlyn bag, and the trigger head. The liquid is held

to see if contamination has entered via the trigger spray head. Test method:

inside the bag and the function of the bottle is simply to enclose and protect

A 1-litre bottle was set up with a HEPA filtered inlet and an outlet connected

the bag in use.

to a Lighthouse Remote 5104 particle counter and an air pump via tubing as

The trigger head operates as a non- venting type, but has unique features

illustrated in Figure 2. The HEPA filtered inlet was necessary to prevent the

with patents pending. The trigger drives a piston in the chamber of the trigger

collapse of the bottle. Air was drawn through the system at a rate of 1ft3/min.

head. When the trigger is squeezed, the liquid in the chamber is forced out of

Background count: The test system was first of all set up without a trigger

the spray nozzle while a nonreturn valve prevents liquid going back down the

head in place, i.e. with the bottle neck open (Figure 3), and three samples were

dip tube. When the trigger is released, the resulting suction draws the liquid

taken for a period of one minute each. The data from these samples indicated

from the bag via the dip tube into the chamber ready for the next squeeze.

the potential airborne contamination challenge level at the bottle neck at the

The integral bag collapses as the liquid is used and a vacuum is formed,

start of the testing (Table 1).

ensuring that all the contents can be dispensed. Two small holes in the base of the bottle allow the air pressure to equalise with ambient, thereby preventing the bottle from collapsing.

The only point of entry into the bag is via the dip tube, which is completely sealed by the trigger head, thereby creating a closed system. This prevents any air being drawn back into the liquid in the bag when the trigger mechanism is operated.

By contrast, in a conventional trigger spray bottle, there is no bag and the trigger spray head is of the venting type so as to allow air back into the bottle to replace the liquid drawn up.

Again, this is to prevent the bottle collapsing, but in this case the liquid is in the bottle, so can be contaminated by the air drawn in.

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

www.farmacom.com.pl

Figure 2: (Below) Diagram of test set-up

1/2012

Figure 1: SteriShield Delivery System

36 | production the liquid when using the new system (Table 5). Two different batches of trigger head were used.

•

Trigger heads used by other suppliers to the life science cleanroom market, triggers X and Y. This test was to compare the performance of competitive products (Table 6) and the SteriShield Delivery System.

Upon inspection, trigger X was non-venting, trigger Y was found to have a venting hole and trigger Z was also a venting trigger with, it was claimed, a filter for the returning air. Environment results: The environmental results

Figure 3: Bottle connected to the particle counter with bottle neck open

given in Tables 1 and 2 clearly demonstrate that there was potential for contamination from the background environment. The results are comparable to the EU GMP standard for a Grade D cleanroom.

In addition, the environmental readings at the end of the test work were of a similar level to those at the start. This shows that the test work itself did not change the level of contamination in the background air and >0.5 micron particles/m3

Figure 4: Bottle connected to the particle counter with trigger head under test in place

>5 micron particles/m3

Test 1

1,071,373

14,535

Test 2

1,065,758

13,903

Test 3

1,073,156

13,457

Table 1: Background count (pre-testing)

Following the testing, the three background counts (with the trigger head >0.5 micron particles/m3

removed again) were repeated to confirm the process had not cleaned up the testing environment (Table 2). This was not possible with Trigger Z as it had a tamperproof neck. However, counts were taken with a new bottle at each trigger change and at the end of the process.

Test system with trigger: The trigger under test was attached to the bottle

>5 micron particles/m3

Test 1

1,645,180

13,977

Test 2

1,778,118

20,432

Test 3

1,825,984

27,810

Table 2: Background count (post testing)

(Figure 3) and air pulled through the system via the pump until a zero count Trigger A

was reached showing the air inside the bottle was now completely clean. The

£0.5 micron particles

trigger was then used for approximately one minute with the same number of actuations that would be required to remove 100ml of liquid. (The number of actuations was calculated from the dispense volume of the trigger). The particle count reading for this one minute period was noted.

The system was then left with the pump running but the trigger not being

Trigger A1

Test 1

Test 2

Test 3

Test 1

Test 2

Test 3

1.1

0

0

0

0

0

Trigger A2

0

0

0

0

0

0

Trigger A3

0

0

0

0

0

0

Trigger B

used in order to allow the air in the bottle to clean up (at rest result). Once a

£0.5 micron particles

zero count had been achieved, usually within the next minute, the test could be repeated. The air was then allowed to clean up again and the test repeated.

For each trigger type a sample size of three trigger heads was used. For each trigger head the test was repeated three times giving a total of nine results per trigger type.

The following tests were carried out: •

Test 1

Test 1

Test 2

Test 3

Trigger B1

0

0

0

0

0

0

0

0

0

0

0

0

Trigger B3

0

0

2.1

0

0

0

Table 3: Negative controls – non-venting triggers Trigger P £0.5 micron particles

no air passes through the trigger at all - in effect the trigger is acting Trigger P1

£5 micron particles

Test 1

Test 2

Test 3

Test 1

Test 2

Test 3

1,021

774

821

2.1

2.1

0

leak-tight and no background air could get into the system in any way

Trigger P2

1,466

1,281

951

0

00

0

(other than through a faulty or venting trigger head) (Table 3).

Trigger P3

1,080

535

790

1.0

0

1.0

Trigger Q

Positive control - standard venting trigger heads from two different

£0.5 micron particles

manufacturers, triggers P and Q. A standard venting trigger allows air to return into the bottle to prevent it from collapsing. This test was

•

£5 micron particles

Test 3

Trigger B2

manufacturers, triggers A and B. A non-venting trigger is designed so

•

Test 2

Negative control - non-venting trigger heads from two different

as a cap on the bottle. This test was to show that the test system was

£5 micron particles

£5 micron particles

Test 1

Test 2

Test 3

Test 1

Test 2

Test 3

2,263

2,670

1,557

5.3

8.4

4.3

to show that if background air is getting in then the test system can

Trigger Q1

detect it (Table 4).

Trigger Q2

1,788

2,171

1,701

9.5

6.3

7.5

The new SteriShield Delivery System, which acts as a non-venting

Trigger Q3

1,450

2,680

1,667

3.2

8.4

3.2

trigger head. This test was to show that no air can be drawn back into

1/2012

Table 4: Positive controls – standard-venting triggers

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

www.farmacom.com.pl

production | 37 that the potential to draw contamination into the system still remained high

Batch 1

at the end of the testing (i.e. passing air through the HEPA filters had not

£0.5 micron particles

£5 micron particles

Test 1

Test 2

Test 3

Test 1

Test 2

purified the air in the background environment enough to reduce the risk

Trigger 1

0

0

0

0

0

0

of contamination). Trigger results: Negative control non- venting trigger

Trigger 2

0

0

0

0

0

0

(Table 3). The negative control results (for non-venting triggers) showed that the

Trigger 3

0

0

0

0

0

0

test system was operating as a closed system. There were no leaks anywhere

Batch 2

£0.5 micron particles

in the system that could contribute to air getting into the bottle. So for any other trigger type, if there were particle count readings it had to be because air was getting in through the trigger.

It was the opinion of the particle monitoring equipment manufacturer that fewer than five particles at the 0.5pm size would be as a result of disturbance

Trigger 1

results demonstrate that the test system was able to detect background air getting into the bottle. They also confirm earlier work carried out by the company using media tests, which showed that with a conventional trigger spray air does get pulled back into the bottle and therefore into the sterile fluid.

The average results for trigger P were 968.80 >0.5pm particles and 0.71 >5pm particles. The average results for trigger Q were 1994.31 >0.5pm and 6.22 >5pm particles. These results are for the number of actuations required to remove 100ml of liquid. Therefore, the results should be multiplied by 10 to show the total contamination in a full 1 litre bottle.

Thus a full 1 litre bottle using trigger P would contain 9,688 >0.5pm particles and 7 >5pm particles and trigger Q 19,943 >0.5pm particles and 62 >5pm particles. SteriShield Delivery System trigger: The SteriShield Delivery System trigger result Table 5 demonstrate that no air passed through the trigger back into the bottle. Zero particle count results were obtained for each replicate, for each of

Test 1

Test 2

Test 3

Test 1

Test 2

Test 3

0

0

0

0

0

0

Trigger 2

0

0

0

0

0

0

0

0

0

0

0

0

Table 5: New SteriShield Delivery System triggers £0.5 micron particles

system. Positive control: standard-venting trigger (Table 4). The positive them) clearly show higher counts of particles drawn into the bottle. These

£5 micron particles

Trigger 3

of any particles within the bottle and should not be attributed to leaks in the control results (for standard-venting triggers where air can pass through

Test 3

Test 1

Test 2

Test 3

£5 micron particles Test 1

Test 2

Test 3

Trigger X1

0

0

0

0

0

0

Trigger X2

421

15

103

4.2

1.1

0

Trigger X3

0

0

0

0

0

0

Trigger Y1

249

64

123

0

2.1

2.1

Trigger Y2

368

82

82

24.6

0

0

Trigger Y3

105

100

150

2.1

0

0

Trigger Z1

28

26

74*

4

4

15*

Trigger Z2

62

353

56

0

21

8

Trigger Z3

189

25

251

21

1

29

Table 6: Other triggers on the market (X, Y & Z) *In these two tests it was noted that the trigger and bottle combination were unable to clean up after use. This indicated that the use of the trigger had compromised it permanently. (There was no evidence of any damage to the trigger)

The result is for the number of actuations required to remove 100ml of liquid so the results must be multiplied by 5 for triggers X and Z, and by 9 for trigger Y, to take account of the respective bottle volumes so as to give a representative figure for complete evacuation of the product.

the three triggers used. Therefore, the trigger does effectively prevent airborne

This would give an average result of 299 >0.5pm particles and 3 >5pm

contamination entering the sterile fluid. Other suppliers’ triggers (Table 6): It

particles being pulled back into the sterile fluid for trigger X, 1323 >0.5pm

is possible to argue that as this was a test of the trigger not the system, there

particles and 30.6 >5pm particles for trigger Y and 591 >0.5pm particles and

could have been a potential incompatibility between the trigger head and the

55 >5pm particles for trigger Z.

bottle leading to air getting into the system. However, even though the triggers

The results from this validation study show the very real risk of compromi-

were different, the actual closure was the same size for all the triggers tested

sing the contents of a sterile trigger spray bottle by the use of a venting trigger

and a good seal was achieved. The fact that the bottle was able to be cleaned

system or of an unvalidated non-venting trigger system. This is highlighted

up to zero particle counts at rest shows that if any air was getting in it was

by the results from the positive controls, using conventional venting trigger

getting in through the trigger in use and not through the threads on the closure.

spray heads, and from the tests of other venting and non-venting triggers.

Trigger X was a non-venting trigger. It was therefore not expected to allow

The results from the tests on the supplier Y trigger showed that air could

any air to be drawn back into the bottle. The results show that this was indeed

get back into the bottle. This was, therefore, not truly a closed system and

the case for triggers 1 and 3. However, the unexpected result for trigger

could not be relied upon to provide a sterile product throughout use.

2 suggests that that trigger might have been faulty.

The results from the tests on the supplier Z trigger showed that the air

Trigger Y showed a significant number of counts for both 0.5pm and

was not filtered sufficiently and potential contamination could get back into

5pm particles; results were comparable to the positive control, therefore air

the bottle. This was, therefore, not a solution to the issue of ‚suck-back’ and

must have been passing back through the trigger into the bottle potentially

could not be relied upon to provide a sterile product throughout use.

compromising any sterile fluid.

The newly developed trigger head used on the SteriShield Delivery

Trigger Z showed a significant number of counts for both 0.5pm and

System has clearly shown that no air is drawn into the system, therefore

5pm particles giving results comparable to or worse than the positive

preserving the integrity of the contents and providing a sterile product

control. The product was supposed to filter the returning air. However, the air

throughout use. These results are further confirmed through conventional

passing back into the bottle through the trigger was not filtered sufficiently to

media testing on the new trigger, which showed no contamination of the

remove particles of concern in a cleanroom environment, therefore potentially

product after three months of rigorous testing.

compromising any sterile fluid.

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

www.farmacom.com.pl

1/2012

38 | production

Electrostatic in pharmacy Entro

Static electricity in the pharmaceutical industry can create manufacturer

Form Fill Seal Machinery

difficulties or be a source of troubles. Below we will discuss these two aspects of the phenomena of electrostatics.

Problems caused by static in the pharmaceutical industry are very wide. Starting from blister packaging, bottle conveying and palletising, labelling, machines forming, filling and closing packaging’s, production of bags, medical finishing etc.

The main problems caused by high static level are: •

process control

•

maintenance of the required quality of the final product

•

dust and powder on the products

•

electric shocks

Maintenance of the required quality of the final product Financial results caused by uncontrolled electrostatic charge are nume-

Problem: Static charges are generated when packaging film is fed from a wind off roll. The major problem is that the product to be packaged is statically

rous and varied. Static electricity can force producers to operate machines

attracted to the inside of the film and prevents proper sealing.

at much lower speeds. This is because static electricity may be direct cause

Solution:

of production problems, such as adhesion of the particles of product in the

Installation of 915 Ionising Bars before the forming collar and just before

package, or inappropriate behaviour during the process of film wrapping, etc.

the sealing bar will prevent product attraction and allow effective sealing.

Static charge can also cause problems when handling, palletizing or labelling a product. Static charge will cause the sticking of packaging material, or

Blister Packaging

sticking to the rollers and the frame of the machine, ausing errors in labelling, counting production and the slowing down of the machine.

Dust and powder on the products The attraction of the contamination present in the air by static charge on the surface is becoming a critical problem as quality standards rise in enterprises.

Dust particles attracted by static electricity can contribute to a high and costly break in production. This is especially noticeable when the material is used in

Problem:

the medical industry, in particular for the production of packaging and medical

•

instruments. There are many solutions to help overcome all these problems.

Static charges during unwinding of the film and the thermoforming process can result in the following problems:

Starting from the simple and effective electrode slot and blowers neutralizing

•

Dust attraction to the film.

static charge to high-quality feedback system that automatically continuously

•

Product misfeeding in the blister.

controls the level of electrostatic charge and immediately neutralizes it.

In the pharmaceutical production process there can also be shown a

Solution:

need for applying an electrostatic charge that holds/connects two or more

Long range 976 Pulsed DC Bars provide effective neutralisation of the

elements together without any „foreign” materials or substances. It appears

static charge at the unwind roll to prevent dust attraction and after the

in the process of IML labelling - because of the purity and selectivity of

thermoformer to prevent product misbehaviour. This solution is ideal for

pharmaceutical processes deserves special recognition.

medical or food packaging as no air assistance is required.

1/2012

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

www.farmacom.com.pl

39 Assambling

Bottle Conveying and Palletising

On blister parking lines friction is caused during transportation causing a very strong electro static charge to appear on the tablets themselves.

This results in the very slow, or not at all, free fall of tablets to the hoppers. The result is a significant‚ slowdown on the machine.

The situation was much worse by blisters plastic trays, which attracted electric charge and on which tablets were to be packed.

The use of ionizing bars neutralizing the static charge on the trays and flexible ionizing nozzles removing static electricity directly from the tablets has eliminated the problem.

Problem: Highly charged bottles from the moulding and conveying process suffer the following problems: •

Dust attraction and contamination.

•

Bottles repel each other causing them to fall over, jump the conveyor guide rails or repel from the final palletised stack.

•

Severe operator shocks.

Solution: A pair of 976 Pulsed DC Bars installed over the accumulator will effectively neutralise the static charges as they are being created by the friction between the conveyor belt and bottles.

Alternative installation positions are also available. (Please contact

Flexible ionizing nozzle removing static electricity directly from the table.

ADVERTISEMENT

Meech).

Bottle and Part Clearing Alternative

lnverte’d.Bototlnea s C onveyor 957 lonising Air Curtain

957 lonising Air’Curtain

261 Ion Nozzles

Salt City Pharma Center provides specialized services in Regulatory Affairs and Pharmacovigilance. We have many years of experience, what allows to accomplish your goals in optimal and effective way.

Problem: Statically charged blow molded plastic containers such as bottles can attract dust and other contaminants. This is a particular concern for the food and beverage industry.

Solution: •

For cleaning the outside of a the container, a series of Ionising Air Curtains can be used. [A]

•

If you want to register a medicinal product / cosmetic / food supplement in Poland or need assistance in the field of Regulatory Affairs and Pharmacovigilance, contact us.

For interior cleaning, pinpoint Ionising Nozzles are used to blow a stream of ionised air into the container. [B] Note; For cleaning of larger parts, the JetStream Air Knife System

can be used.

Medicinal Products • Preparation and evaluation of dossier • Registration in Poland under national or European procedure • Surveys of medical literature databases and professional journals in the field of Pharmacovigilance • Preparing PSUR • Regulatory Affairs Consultancy • Medical Translation Medical Devices • Preparation of documentation according to the classification of the device and application and coordination of application / notification process Food supplements / Foodstuff for particular nutritional purposes/ Cosmetics • Preparation of documentation and coordination of the registration process

Salt City Pharma Center Joanna Organiściak-Płachta d o w n l o a d *. p d f v e r s i o n :

www.farmacom.com.pl

Wieliczka 32-020, Grabówki 278, + 48 500-060-896, joanna.organisciak@scpc.pl, www.scpc.pl

advertorial

40 | production

Kujawskie Zakłady Poligraficzne

Druk-Pak S.A.

– leader in the production of pharmaceutical packaging in Poland

Kujawskie Zakłady Poligraficzne Druk-Pak S.A. is a well-known and undisputed leader in the production of pharmaceutical packaging in Poland. The company concentrates in its philosophy primarily on customer satisfaction through stability and excellent quality, especially required in such a branch of industry as pharmacy.

Piotr Orliński Deputy Production Manager for Investment and Technical Issues in KZP DRUK - PAK S.A.

An essential mainstay of the company is extensive knowledge and

backed by the knowledge and experience of production engineers allow

experience of the employees supported by a modern machinery park. The

to make even the most innovative changes.

fact that the preparation of the production is completely independent of

The period 2010-2011 for many companies was the period of the crisis.

external companies, allows for the openness and flexibility in accepting the

However, for Druk Pak this was the time of the most visible expansion.

most complicated orders. Even in times of crisis, when many companies

In October, three new buildings were put into service: a modern social

act in a very conservative way, and watch every penny many times,

building, and two modern production halls. A key project is a modern

Druk-Pak makes substantial investments by strengthening its workforce,

production hall, which was designed under very restrictive requirements for

its machinery park, and its building infrastructure.

the pharmaceutical production, and in accordance with the existing printing

To meet the needs of pharmaceutical clients, DRUK-PAK S.A.

standards. Huge financial investments have been allocated to the policy of

implemented a certified Quality Management System ISO 9001, 14001 and

air management, which in many printing-houses is set aside, most often

as one of the first printing companies in Poland, ISO 15378, based on the

due to the lack of funds. The new hall is equipped with fully standardized

principles of GMP. Moreover, the production is carried out in compliance

lighting and automatic monitoring of temperature and humidity.

with the rules of the standard PN - EN 15593 „Management of Hygiene

KZP Druk-Pak S.A. also invested in a modern six-colour printing press,

In the Manufacture of Packaging For Food Products”. Consistent actions

printing in B1 format with two coater modules, and the automatic control

associated with the development of these standards have allowed the

system of colours on the sheet. The device can apply UV paint to a whole

company to achieve a rich organizational culture based on the cooperation

sheet, on a selective basis, create hybrid effects on cardboard or on

between the employees and the management staff. It is significant that the

non-absorbent surfaces. The technology also allows for a wide range of

actions that initiate the development of Druk-Pak often come from the very

security applications such as special protective varnishes and pigments,

employees, who daily experience production problems, whereas solutions

paints invisible for a bare eye, the coin reactive effects, and many others.

1/2012

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

www.farmacom.com.pl

41

The press is connected to the prepress, where paint profiles are generated,

the labels segment. Besides the efficiency, the safety of the production is

considerably allowing to shorten the time for the preparations of orders.

controlled by one hundred percent quality control module that can detect

All the printing machines are connected into a network and into the main

even impurities in the raw material, and an inkjet label numbering system.

database, from where all settings are taken in case of reprinted orders. This

An innovation in the scale of the entire country proved to be a new

gives confidence to the customer and ensures a complete reproducibility of

folding and gluing machine, Diana, with a ROTO-Braille module. Although

information on other machines if a given machine is turned off. The colour

the rotary Braille application is quite popular in Poland, the ROTO system

control system installed in a new press (as in all others the company has)

purchased by Druk-Pak, is the result of several individual tests and

allows to quickly measure the characteristics and make the necessary

modernizations of the tools in order to obtain high quality products and

adjustments to minimize waste production. The purchase of this press has

thus the customer satisfaction. This system of Braille application on many

been funded through the project „The increase of competitive enterprises

sides at once, popular in Europe, connected with the quality control system

in relation to KZP Druk-Pak S.A. in Aleksandrów Kujawski as the result

in the machine is an invaluable support in the production of packaging.

of investments in innovative printing equipment, which was co-financed

Druk-Pak S.A. is one of the few printing companies in Poland that have

from the state budget under the ROP WK-Q for the period 2007-2013”.

a specialized software, PHARMA PRINT CONTROL for electronic compa-

A supplementary machine to the printing press is Bobst shearing machine

rison of compliance of the files prepared for the production with reference

with a full preparation of the production outside of the machine. This

files (patterns), for verifying accuracy of the content of the Braille characters

investment is the seventh improvement of the die-cutting machinery park

and their readability, and for verifying the correctness of bar code printing.

in Druk-Pak. In addition to die-cutting, the company can offer hot stamping

The purchase of this program was dictated by the assumptions of the quality

and application of holographs.

policy implementation and was the result of guidelines for a development

Despite such a significant improvement, a novelty in Druk-Pak is a

strategy of the enterprise. Moreover, this investment was in response to

smaller-size press for printing self-adhesive labels. The implementation

clearly defined customer expectations for safety of their products at the

of flexographic technology at the plant fills the gap in production services

preparation stage for the production. The program, expensive to purchase

for pharmaceutical companies. A modern, eight-colour narrow web

and implement, allowed for an even better monitoring of the preparatory

Gallus printing machine, printing in the UV technology with a machine for

process, and improved the customer service at the pre-production level.

packaging the printed labels is the foundation of the production capacity in

More information is available on the website www.drukpak.pl

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

www.farmacom.com.pl

1/2012

42 | production

Case study

Process Train Containment in CMO Operations Michał Jaworski SYLKAT s.c. www.doverpac.com

Pharmatek Laboratories, Inc. is a premier pharmaceutical chemistry development organization supporting the pharmaceutical and biotechnology industries.

Pharmatek offers development and manufacturing services for

nulation, Oven Drying, Fluid Bed Drying, Milling, Blending, Encapsulation,

highly-potent and cytotoxic (HP/C) compounds including:

Tableting and De-dusting are all examples of manufacturing processes in

•

Analytical methods development

which Pharmatek has integrated the ILC Dover containment technology.

•

Stability storage and testing services (all ICH storage conditions)

•

Preformulation testing

combined with their state-of-the-art HP/C facilities, ensures their customer’s

•

Formulation development

molecules move efficiently from discovery to clinical trials.

•

Technical transfer for commercialization

•

GMP manufacturing of phase I/II clinical supplies

•

Clinical distribution and fulfillment

Pharmatek’s focus on pharmaceutical chemistry development,

Pharmatek focuses on preclinical and early-phase development & manufacturing of small molecules and peptides.

How do flexible enclosures work?

Handling HP/C compounds requires highly specialized facilities and controls. As part of Pharmatek’s overall corporate safety program, they

Flexible Containment Enclosures are designed using two basic methods - flange mount and total encapsulation.

have chosen after careful consideration to integrate ILC Dover Flexible

The flange mount approach is used for the tray dryer where the flange is

Containment Solutions into their HP/C facilities. Wet Granulation, Dry Gra-

added to the face of the dryer outside of the door. An enclosure made from

Late Stage Discovery

Pre-Clinical Development

Phase I

Phase II

Phase III/ Commercial

IND*

Compound Selection Preformulation API Method Development Method Qualification GLP Formulation Support

*

Formulation Development Drug Product Methods/Specification Prototype Stability cGMP Manufacturing/Packaging/Labeling Release & ICH Stability CTM Storage & Distribution

IND – Investigational New Drug

1/2012

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

www.farmacom.com.pl

43

Photo 2. Solid Pan Mount Total Encapsulation. Selected for Granulator

Photo 1. Flange Mount Flexible Containment Selected for Tray Dryer

ILC Dover Enclosure System

Test Material

OBZ-TWA* (Mg/m3)

Comment (No. of operators)

Granulator

Lactose

0.0026-0.0027

Operation (2)

Granulator

Lactose

0.0027-0.0331

Cleaning (2)

Drying Oven

Lactose

0.0026-0.0028

Operation (2)

Drying Oven

Lactose

0.0026-0.0037

Cleaning (3)

Based on surrogate monitoring testing conducted by Kasai Consulting, Pharmatek’s facilities in San Diego achieved the nanogram containment values shown at left.

Tab. 1. *Operator Breathing Zone - 8 Hour Time Weighted Average

the rugged ArmorFlex® family of films is then attached to the flange and a

•

Supports lean manufacturing - with over 100 product runs per

supporting frame assembly. The door is within an enclosed environment

year, Flexible Containment supports easy product changeover

when loading and unloading the trays with the drug product.

and helps Pharmatek meet stringent EH&S requirements and project timelines.

The trays, drug product and associated process tools can either be

•

preloaded into the enclosure or bagged into the isolated area via bag in/

Superior operator protection - proven nanogram level containment (reference table above)

bag out (BIBO) canisters or larger drum ring attachment canisters.

For the wet granulation process, Pharmatek selected the total encapsulation method by working with ILC Dover engineers.

Additional advantages •

Durability - manufactured using puncture resistant ArmorFlex® films,

•

Improved ergonomics - the flexibility of the enclosures in terms of

Solid pan mounted enclosures allow the entire piece of process equipment to be contained. The enclosure is supported by an elastic

the enclosures hold up during the most demanding operations.

suspension system, attached to the pan, and includes glove sleeves

configuration (glove sleeves, ports, and passthrus configured for the

for access to the equip- ment and integrated HEPA filters. Based on the

equipment), the film clarity, and the elastic suspension attachments

suspension system, the operator is able to get in close proximity to the process, as if containment wasn’t even present.

simplify the process for their operators.

•

Custom designed - with ILC Dover’s engineering expertise, Pharmatek custom designs enclosures for each process train unit.

What are the applications?

Flexible Containment enclosures have applicability across Pharmatek’s

What containment level is provided? (Tab. 1.)

entire high potency process train.

Why flexible?

What are the key benefits of this technology?

•

Flexible Enclosures prevent cross contamination and help

Prevents cross contamination - the enclosures are single-use and are

assure operator safety in Pharmatek’s development and manufacturing

dedicated to a specific compound to prevent cross contamination,

operations.

which is of extreme importance to their customers.

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

www.farmacom.com.pl

1/2012

44 | logistics

Modern warehouse in the pharmaceutical industry Marcin Figlarek Consafe Logistics

A standard warehouse contains thousands of shelves, where tens or even hundreds of thousands products are stored. Management of such enormous product quantities turns out to be a particular challenge, especially in the pharmaceutical industry, where possible distribution error may cost the health or even life of patients. This is why companies cannot do without state of the art warehouse management solutions.

The pharmaceutical industry has certain particular requirements which force drug manufacturers and all links of the sophisticated distribution chain to maintain absolute order and process accuracy. The foundations of quality and effectiveness are full control over the system and insight into its smallest elements. The way from the drug manufacturer to the end recipient – namely, the patient – is a multi-stage and complex journey, which requires solutions enabling registration of slightest goods movements, accelerating their circulation and increasing delivery accuracy.

Restrictive logistic processes force drug distributors to use state of the art packing and transport technologies to eliminate possible human error from logistic processes. In fact, experience shows that the human factor constitutes the weakest link of the whole process; therefore, an efficient IT system is nowadays the sine qua non condition of effective distribution and warehousing of drugs.

In the warehouse jungle Imagine a huge warehouse containing a countless number of pallets

temperature or humidity. That is why WMS solutions, designed specifically

on which hundreds of carton boxes are placed with lots of small indivi-

for the pharmaceutical sector, include so-called product arrangement

dual boxes of drugs inside. For efficient management of such enormous

algorithms, which ensure strict monitoring over storage and shipments

quantities and minimising the risk of error, both logistic companies and

and allow avoiding staff errors.

warehouse owners are implementing systems to support management of

Large scale errors in the distribution of drugs may cause paralysis of

warehouse space – so-called WMS, i.e. Warehouse Management Systems.

almost the whole health care system. That is why our safety is nowadays

Proper operation of the warehouse system determines effective functioning

guarded by state of the art IT solutions. A modern warehouse is a

of the whole supply chain.

smoothly operating organism whose heart is the server collecting and

Nowadays, when the importance of time is growing and production

distributing information among warehouse employees. What is, therefore,

line downtimes are no longer caused by hours but by minutes of delay,

the essence of goods management in the warehouse? In fact, each – even

efficient warehouse management is one of the key factors determining

the smallest – collective carton box is identified with a unique SSCC (Serial

success of the enterprise. In case of pharmaceutical products, this issue

Shipping Container Code) code, which is a recommended solution in the

is even more complicated as the storage regime is much stricter than, for

pharmaceutical market. SSCC codes are unique in the global scale, no

example, in the case of food. There are certain kinds of drugs that cannot be

matter how small the consignment is and no matter how small the wholesale

stored next to one another, which cannot be stored in a too low or too high

unit or warehouse where it is stored is. What is more, separate scanning

1/2012

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

www.farmacom.com.pl

45 is sometimes taken over by RFID solutions, whose advantages include fast operation and lack of identification errors. However, the process is proceeding relatively slowly because of much higher costs connected with implementation of that technology.

WMS solutions are developed and implemented by specialised IT companies. It is highly recommended to use the services of an integrator that will ensure comprehensive implementation, i.e. that conducts the system implementation process from the stage of designing the system of storage and internal transport until final configuration of the IT application software.

One ought to bear in mind that one of key issues related to development of the discussed solutions is utmost care about the quality of equipment.

The most important elements include portable terminals, which ought to ensure uninterrupted operation throughout their life. Savings should not be sought when purchasing such devices, also because they will operate in difficult conditions and will be exposed to shocks or even falls from considerable heights.

Moreover, a modern warehouse ought to be equipped with access points, allowing wireless communication from any place between terminals and the server. This allows significant shortening of the time needed to reach a specific place, and employees obtain access to a whole spectrum of information they may need at a given time. So-called voice-picking – through which a warehouse employee only communicates with the system verbally – is becoming an increasingly popular technology. The system issues a voice command, the employee only needs to confirm the quantity and location, also verbally, and the information is transferred to and recorded in the central system. This solution is being chosen by a growing number of companies, as it leaves the employee’s hands free and gives him or her considerable freedom of movement. Independent research proves that voice picking allows growth in productivity by 5 to 15%. What is more, this technology significantly reduces the number of

tgw-group.com

error to no more than 0.5 per 1000 picking lines.

of each individual box is not needed, but content of the whole collective carton is scanned and the collective carton is identified in detail already at the beginning, including its content.

Warehouses storing drugs are frequently equipped with warehouse automation solutions, which minimise the number of activities performed by people. This is aimed at further reduction in the total number of errors.

An automatic placement machine or shelf rack correctly perform instructions received from the WMS. The WMS provider must have extensive experience in integration with such equipment.

In the case of the pharmaceutical market, monitoring of expiry dates is a priority. Warehouse employees have quick access to a database where information concerning expiry dates of a given drug is recorded. Delivery of

WMS: in agreement with industry requirements

an appropriate batch to the recipient is the responsibility of the warehouse

A WMS class solution is designed taking into account individual

system. WMS prevents such occurrences in which the same drugs with

needs of a given enterprise. Consequently, systems differ from one

shorter expiry dates stay on the shelf, whereas drugs with longer expiry

another depending on the requirements, application and complexity of

dates are delivered to customers. The system eliminates such errors and

the processes they handle. However, a certain schematic plan of a WMS

protects the company from possible compensation liability.

structure can be outlined. The WMS includes software installed on the

The risk of human error is enormous. That is why companies, not

server of the whole system, equipment for automatic identification (barcode

only logistic ones, more and more often decide to implement the WMS.

readers, RFID) and communication environment (e.g. radio communication,

Illusory savings or omissions frequently cause losses, not only in terms

wi-fi), which links all those elements into a complete system. Moreover,

of money, but also in terms of image. Thus, it is a good idea to consider

an indispensable element are barcode printers, which allow fast and easy

implementation of a system which will eliminate the risk and really improve

identification of all logistic units in the warehouse. The role of barcodes

the company’s competitive position.

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

www.farmacom.com.pl

1/2012

46 | reports, projects, plans

Polish dietary supplements market to reach PLN 2.5bn by 2012 Monika Stefańczyk Head Pharmaceutical Market Analyst, PMR Publications

In 2011-2013, the market of dietary supplements in Poland will develop at a rate of 9-15% annually, according to the latest report published by PMR entitled „Dietary supplements market in Poland 2011. Development forecasts for 2011-2013”. Although the market growth rate is lower than in the preceding year, it should be noted that it still will be very high, e.g. higher than the rate for OTC medicines. PMR assumes that the trends which prevailed in the previous year and positively stimulated sales will continue. These trends include the aging population, growing interest in self-treatment, healthy lifestyle and healthy appearance, natural and herbal products.

Weak 2010 In 2007-2010, a growth rate of the Polish dietary supplements market gradually flattened to equal merely 4% in 2010, hitting a ten-year low. Generally, in 2010 the whole pharmaceutical market, including manufacturers of health products, such as dietary supplements, reported relatively low growth rates. This was mainly a result of a high base effect of 2009, when due to a large number of infections and a panic caused by swine influenza, sales of OTC products climbed notably in spite of the global financial crisis. At the same time the 2010 growth rate was adversely affected by the economic crisis in Poland and although the GDP doubled relative to 2009, Poles’ purchasing power was still rather weak.

Additionally, companies were forced to reorganise their product portfolios since regulations regarding borderline products became effective. According to the PMR research conducted specifically for the report, approx. 10% of companies had to withdraw a part of their products as a result of the regulations.

Companies approach future with greater caution The majority of the companies predict that their financial condition will improve in 2011. However, this involves a 23 p.p. plunge relative to 2007. What is more, four years ago none of the companies expected their financial situation to deteriorate, whereas this year 6% of the respondents make such a prediction. Additionally, approximately one-third of the interviewed forecast that in 2011 their company’s financial standing will remain unchanged. This proves that in comparison with 2007, the respondents’ mood are slightly more moderate, but still rather positive.

Methodological notes: In September 2011 PMR Research – the research arm of PMR (www.research-pmr.com) – conducted a survey among the management of around 190 companies engaged in dietary supplements trade in Poland.

The survey was conducted by telephone and a total of 97 telephone interviews were successfully completed

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The article is based on the report “Dietary supplements market in Poland 2011. Development forecasts for 2011-2013” published by PMR Publications in November 2011.

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

www.farmacom.com.pl