100 %On-lineQualityControlwith X-Ray-Technology · 2012. 7. 19. · tem in the capsule filling machine is executed semi-automatically. After the fully-automatic sensor calibrati-on,

100 % On-line Quality Control withX-Ray-TechnologyDevelopment of a 100 % on-line weight control unit with PATelements forpharmaceutical capsules

Martin Vogt, Melanie Beck, Dr. Iulian Maga . Robert Bosch GmbH, Waiblingen

Correspondence: Melanie Beck, Robert Bosch GmbH, Packaging Technology, Postfach 11 27, 71301 Waiblingen,e-mail: [email protected]

State of the Art

According to the current state of ourtechnology, the capsule filling machi-nes („GKF“) work at a productionspeed of 140 cycles per minute orhigher. Every pharmaceutical com-pany also has the wish to know theexact weight of each and every cap-sule that they produce before it ispackaged, leaves the production faci-lity, and is consumed by the end-user.For this reason, a checkweigher isgenerally placed in-line with the cap-

sule filling machine that weighs thefilled and closed capsules. This is ho-wever not exactly „on-line“, becausethe capsules have to be transported agiven distance from the capsule fil-ling machine to the checkweigher.The relationships between the cap-sule fill-weights and the filling pro-cess is therefore difficult to correlate,since the capsules are not indexedduring transport from the capsulefilling machine to the checkweigher.Dosing modifications in the capsulefilling machine according to check-

weigher feedback can therefore onlyhappen on a time-delay and onlylong-term weight trends can be re-cognized and compensated for.

A partial improvement can berealized by utilizing an in-processcontrol scale. This unit is capable ofremoving capsules from the encapsu-lation process during full speed pro-duction and gravimetrically weighingthem individually. It takes a few mi-nutes to weigh a full segment of 10capsules (on a mid-speed capsule fil-ling machine), however the user gets

Authors

Melanie Beck

Melanie Beck (Dipl.-Ing. (FH) ) is a product ma-nager at Bosch Packaging in Waiblingen, where sheis responsible for capsule filling machines andcheckweighers. She completed her university stu-dies with a thesis project at Bosch in 2007 in thefield of Pharma Technology. After her studies shebegan as a validation engineer at Valicare withinthe Bosch group. Since 2009 Melanie has beenworking in her current role as a Product Managerin the Pharma Solid group. In this role she hasspecialized in the development of x-ray and micro-dosing technology, among others.

Dr. Iulian Maga

Iulian Maga (Dr.-Ing. ) studied information systemsin Stuttgart until 1999. Upon completion of hisdegree he began working as a development engi-neer at Bosch Packaging. Iulian completed hisdoctoral work in Automation Technology and In-formation Systems in 2007 at the University ofKlausenberg alongside his work at Bosch. He cur-rently focuses on the development and visualiza-tion of control system concepts for packagingmachinery, the introduction of new technologies inpackaging technology, and the development of newcontrol software for servo motors.

Martin Vogt

Martin Vogt (Dipl.-Ing. ) is a project manager fordevelopment projects in the process control sys-tems field. He completed his university studies inMechanical Engineering in 2008 with a concen-tration in „Process Technology/Machines“. Hecompleted his thesis project with Bosch in 2008and has been working as a design engineer in thePharma Solid group since then. In the R&D de-partment he is responsible for the conceptualiza-tion, design, and testing of process control systemsfor pharmaceutical capsules.

TechnoPharm 1, Nr. 1, 60-67 (2011)© ECV . Editio Cantor Verlag, Aulendorf (Germany) 1Vogt, Beck, Maga . 100% On-line Quality Control with X-Ray

measurement and control technologyEnglish reprint of the German original publication

a very accurate image of the currentdosing of the fill station, because thecapsules are removed from the pro-cess directly after being closed. Theautomatic feedback to the dosingstation based on the fill weights fromthe in-process control can take placequicker, since the time required toweigh the capsules is quite short.This type of weight control is an im-provement, but it remains as simplya „static“ control method. Until nowthis has been the standard state oftechnology, however, it does not trulymeet the requirements of the phar-maceutical industry.

There are currently clear trends innew dosage forms, such as highly po-tent active ingredients or hormonepreparations. Machine builders havereacted to new requirements withoperator-protection and contain-ment concepts. Contained capsulefilling machines generally containan in-process control scale. The wishto have 100 % on-line control is stillhowever unanswered, this time ho-wever with the added requirementto have a solution be completelyWIP and CIP capable (WIP: Wash-in-Place, CIP: Clean-in-Place).

If one considers the weighing cellsof reputable manufacturers that areavailable on the market, there are afew options that can withstand theaforementioned cleaning cycle, butthey have to remain sealed duringthe cycle. In order to reach the requi-red weighing accuracy of the Phar-macopeia during the production pro-cess, as well as to secure the scaleagainst contamination, a very costlyseal-technology is necessary. For agravimetric, 100 % on-line weightcontrol, the weighing cells wouldhave to be placed in the containmentcabin as a block with a special seal.This block would be much largerthan what could be accomodatedfor by a capsule filling machine withstandard dimensions.

Further reasons for not incorpora-ting gravimetric weighing cells intothe capsule filling machine pro-duction cabin are the known factorsof vibration and air currents. These

factors are inevitablewhen introducingweighing cells into amachine that runs ata production speed of140 cycles per minute(meaning 2 capsuleshave to be weighedevery second) andmake a sufficientlyexact weighing pro-cess almost impos-sible.

A Change in PrincipleFollowing the Exampleof Weighing Cells

A change in prinicple promised tosolve the existing issues. The weig-hing cells from a standard laboratoryscale based on the force compensa-tion principle have to refer to a se-condary physical principle in orderto convert the mechanical weighingforce of the capsule into an electri-cally measurable form. In this case,that form is the current that compen-sates the deflection of the coil arma-ture in the solenoid via magneticforce.

So, why not use a different physi-cal principle, in order to make themechanical form of weighing forceelectrically measurable? The Lam-bert-Beersche Law provides somebackground to the situation(Image 1). Under the assumption ofa constant absorption coefficient (μ),it is possible to detect the absorbedamount of x-ray radiation in a testbody via x-ray radiography. In theequation, the radiation intensity (I),which is measured behind a barrier,equates to the undamped radiation(I0 ), with the thickness of the irra-diated material (d) being a variable. Ifyou then take the radiation absorp-tion and relate it to the weight of atest body, which has been gravimetri-cally determined, you can proceedbackwards with these values to de-termine the weight of a second testbody from its radiation absorption,assuming the absorption coefficientof both bodies is identical.

From Theory to Practice

The practical applications of the des-cribed physical principles were firsttested on a static test stand(Image 2). A capsule magazine withan edge length of 50 x 50 mm is pla-ced between an x-ray tube and an x-ray surface sensor. A filled capsulewho’s shell can have any arbitrarycolor, is placed in the magazine.

A digital imageis generated uponthe surface sensorbeing exposed tothe x-rays and thisimage is then eva-luated with thehelp of a speciallydeveloped soft-ware to detect theoutside contour ofthe capsule shell(Image 3). In thefirst step of theevaluation pro-cess, which wassubmitted for pa-

X-RaySource

CapsuleMagazine

X-RaySensor

Image 2: Test Stand Depiction (BoschPackaging).

I = I0 -μ d

Image. 1: Lambert-Beersches Law

Image 3: Contourrecognition of acapsule filledwith pellets(Source: Bosch).

TechnoPharm 1, Nr. 1, 60-67 (2011)© ECV . Editio Cantor Verlag, Aulendorf (Germany)2 Vogt, Beck, Maga . 100% On-line Quality Control with X-Ray


tent, the gray-scale value of every sin-gle pixel within the detected contouris converted to a thickness. The ave-rage of these individual thicknesseswithin the chosen surface is thenmatched with the gravimetric weightof the capsule, which has to be de-termined by a gravimetric weighingsystem. The conversion functionfrom gray-scale value into thicknessis product dependent, since the ab-sorption of the x-ray radiation is de-pendent on the chemical composi-tion of the irradiated material. Theassosciated material constant is theso-called absorption coefficient (μ).See Table 1 and Image 4 for exam-ples. The system must be calibratedfor every product with a differentchemical composition. Once the sys-tem is calibrated for a given product,a stable weight determination ispossible for the entire duration ofa batch. This is also valid even ifthe density of the product filled inthe capsule should vary, for instancedue to a process-related adjustmentof the tamping pressure in the do-sing station. In the case of a higherdensity, more x-ray radiation will beabsorbed and the capsule image willbe darker, and the resulting weight

of the capsule will behigher. When comparingcapsule weights derivedfrom the x-ray processto that of the weightsfrom the laboratoryscale1, the maximumdifference was +/– 2 %.Capsules with a weightrange of 180-440 mgwere used for the x-raytests. The test productswere corn starch powderor glucose pellets, whichare also used by pharma-ceutical companies asstandard test materialsduring machine accep-tance tests (FAT andSAT).

From a Static TestStand to a Multi-LanePrototype Machine

After the promising results on thetest stand, the system was adaptedto the Bosch GKF HiProTect 1700containment capsule filling machine(Image 5, Bosch capsule filling ma-chine with containment) and was po-sitioned at the capsule ejection stati-on. In this machine, 12 capsules haveto be simultaneously handled andevaluated per machine cycle, whichrequired an x-ray surface sensor thatprovided a larger evaluation window.Based on the good experience withthe test stand, the same basic hard-ware was used for the machine adap-tation, however, due to the larger x-ray surface sensor (now with an areaof 150 mm × 50 mm) two x-ray sour-ces were required.

The calibration of the x-ray sys-tem in the capsule filling machine isexecuted semi-automatically. Afterthe fully-automatic sensor calibrati-on, the machine operator must exe-cute the 2-point calibration for thecurrent batch. In this process twocapsule fill weights are generatedthat are ideally slightly above and

below the desired fill weight, re-spectively (this can easily be donewith the help of an adjustable dosingdisk or a changed tamping pressu-re). These over and under-filled cap-sules are then gravimetrically weig-hed by the in-process control (IPK)scale and automatically transportedto the x-ray system. Once the capsu-les reach the x-ray system, all of thecapsules on the image produced bythe x-ray surface sensor are assignedthe gravimetric weights determined1) Type: KERN 770-60

Image 4: Radiation intensity versus material thickness fordifferent absorption coefficients (Source: http://de.wikibooks.org/wiki/Physikalische_Grundlagen_der_Nuklearmedizin/_D%C3%A4mpfung_von_Gammastrahlen).

Image 5: X-Ray Prototype in the GKF HiProTect1700 (Source: Bosch).

Table 1

Examples of Absorptioncoefficients μ [cm–1] (Indescending order: air,water, carbon, aluminum,iron, copper, lead)

Absorber 100 keV

Air 0,000195

Water 0,167

Carbonate 0,335

Aluminum 0,435

Iron 2,72

Copper 3,8

Plumb 59,7


by the validated in-process controlscale.2 According to our experience,this calibration procedure takes nolonger than 30 minutes. At the endof the calibration phase the productspecific density-to-weight calcula-tion algorithm is formulated basedon the in-process control scaleweight results. This algorithm thenallows the gross weight of every cap-sule produced on the capsule fillingmachine during that batch to be de-termined from the x-ray images „on-line“ at full machine speed.

Table 2 shows weight measure-ments that were compiled during atest run with corn starch filled intosize 4 capsules. In this chart, the x-rayweight measurements are comparedto the gravimetric weight measure-ments, which were previously attai-ned using the in-process control scale.The difference between the two va-lues is listed in absolute (milligrams)and relative (percentage) terms. Themeasurement and compilation ofthese weight results is executed auto-matically in the capsule filling machi-ne. Therefore the correct matching ofthe individual gravimetric weights tothe corresponding capsule in the

image is guaranteed and can't acci-dentally be interchanged.

Optimization of thePrototype

The first version of the capsule ma-gazine in the machine was based on aconcept where the capsule was pus-hed through two parallel plastic pla-tes that have a very weak x-ray ab-sorption. A 1 mm thick spring steelplate was used to separate the 12capsule lanes from each other, inwhich the capsule lanes were lasercut from the plate. The main advan-tage of this design is the low cost offormat parts and the short manu-

Table 2

Compilation of x-ray weight measurements and individual gravimetricgross weights measured on the in-process control scale (Capsule size 4,empty capsule nominal weight 38 mg, corn starch fill) (Source: Bosch).

1 Scales (mg)1 X-Ray (mg)1 Difference (mg)1 Difference (%)2 Scales (mg)2 X-Ray (mg)2 Difference (mg)2 Difference (%)3 Scales (mg)3 X-Ray (mg)3 Difference (mg)3 Difference (%)4 Scales (mg)4 X-Ray (mg)4 Difference (mg)4 Difference (%)5 Scales (mg)5 X-Ray (mg)5 Difference (mg)5 Difference (%)6 Scales (mg)6 X-Ray (mg)6 Difference (mg)6 Difference (%)7 Scales (mg)7 X-Ray (mg)7 Difference (mg)7 Difference (%)8 Scales (mg)8 X-Ray (mg)8 Difference (mg)8 Difference (%)9 Scales (mg)9 X-Ray (mg)9 Difference (mg)9 Difference (%)10 Scales (mg)10 X-Ray (mg)10 Difference (mg)10 Difference (%)

Result of Measurement

Nr. Description

Underline

Colour Meaning Variation <=2% 2% < Variation <= 5% Variation > 5%

2) IPK Scale: Bosch 8-104-608-610; Scale accuracy+/–0.2 mg



facturing time required (Image 6).Thanks to the digital sensor, the cap-sules that had a larger than averagedeviation between the in-processcontrol scale weight and the x-raydetermined weight could be targetedand evaluated afterwards on the x-ray image. During these evaluationsit was noticed that the capsules couldbe partially hidden behind one of themagazine plates and therefore couldnot be seen by the x-ray image, norevaluated by the software. This clari-fied the higher than expected varia-tions between the x-ray determinedweights and the in-process controlscale weights of some capsules. Uponexamination, the plate was not evenenough to allow for an accurate andconsistent image to be taken of eachcapsule. A new design, which utilizedonly FDA-approved plastics, allevia-ted the problems with the capsulemagazine (Image 7).

The weight variations between in-process control scale weights and x-ray determined weights were redu-

ced to a maximum of+/– 1 % thanks to thisnew capsule magazinedesign.

UniversalApplicability

The system canhandle all hard gela-tin and HPMC capsu-les in sizes between5 and 00. In individualcases the actual speedof the system could besomewhat reduceddepending on thecapsule size and thefill weight of the pro-duct, however theaverage speed is bet-ween 120 and 140 cy-cles/min. The eva-luations were exe-cuted using cornstarch, lactose powder,and glucose pellets(Image 8). These sub-stances have a similar

atomic composition to that of stan-dard pharmaceutical excipients.They also all have in common thatthey are comprised mostly of car-bon, hydrogen, and oxygen. Theseelements all have a low nuclearcharge and therefore only absorbvery small amounts of x-ray(Image 9). The concentration of theactive ingredient within a product isgenerally a fairly small percentagecompared to that of the excipient,so the influence of the active ingre-dient is negligible, even if its nuclearcharge is higher than that of the ex-cipient. Therefore, the achievedweight tolerances can generallly beapplied to other formulations. If theatomic composition of a product va-ries significantly from the standardexcipients listed above, for instanceif the active ingredient has a largerconcentration, the product shouldbe analyzed individually for weightresult accuracy.

Image 6: X-Ray Image of the Capsule Magazine with Spring-Steel Plate (Source: Bosch).

Image 7: X-Ray Image of the Capsule Magazine Made of all FDA-approved Plastics (Source: Bosch).

Image 9: X-Ray Image of Different Capsule Fills(Source: Bosch).

Image 8: Examples of Capsule Fills (Source:Bosch).


No Negative Impact of theX-Ray Radiation

The influence of the x-ray radiationon pharmaceutical active ingredientsis negligible. As an internal RobertBosch Corporate R&D study showed,the number of active ingredient mo-lecules that were altered due to the x-ray process was maximally in theppm range.

In comparison, storing the sameproduct for a few weeks exposes itto a much higher risk of damage ordegradation of the substance fromnatural and civilian radiation sources(see Table 3).

The x-ray unit is designed as afully shielded system and will receivea „construction method approval“shortly. With this approval, a phar-maceutical company would needneither an operation permit nor aspecialist on-site at all times that isresponsible for the operation andsafety of the x-ray system during pro-duction. The responsible authoritiesmust simply be notified of the use ofthe x-ray system in advance of instal-lation.

There are no health and safetyconsiderations that need to be madefor the operators of the x-ray unit.The maximum radiation exposure le-vel for job-related x-ray exposure willnot be reached from operating thissystem.

From 100 % On-lineWeight Control to aneffective PAT-Tool (ProcessAnalytical Technology)

Anyone looking at these x-ray imagesmight immediately think, „what ot-her PAT applications could this tech-nology have besides determining thecapsule weight?“

Thanks to the capsule magazinemade of only plastic, the capsules arealways comple-tely visible andthe capsule ma-gazine itself ismade to be „invi-sible“ through acouple softwareand calibrationsteps when set-ting up the sys-

tem. Therefore, foreign particles, forinstance glass or metal particles, arealways easily visible and can not pos-sibly hide behind the metal edges ofthe magazine (as could happen inimage 9). Foreign particles can thusbe detected if they have a higher den-sity than the product being evaluated(meaning the absorption coefficientis higher). The minimum particle sizethat can be detected by the systemdepends on the enlargement factorof the image (distance between x-ray emitter, the product, and the sen-sor), as well as the pixel size of the x-ray sensor. Furthermore, damage tothe capsule cap and body are recog-nizable, as two adjacent capsules willoverlap in this case. The system canalso measure the capsule length and

Table 3

Examples of different radiation exposure levels due to varying activities

Lethal dose

Radiation Sickness Threshold

1 hour stay at the melted down Fukushima reactor

1 year stay in Guarapari (Brazil)

Yearly maximum allowable exposure level in the workplace

1 Computer tomograhy image at the chest

1 year stay at Katzenbuckel, Germany

1 year stay in Germany with medical tests

1 x-ray image of the spine

1 year stay in Germany with only natural radioactivity

Yearly maximum x-ray exposure for the general population

250 work days with 8 hour shifts working with the capsule x-ray inspection system

1 return flight FRA-SFO

1 x-ray image of the chest

Image 10: With stainless steel capsule magazine (Source: Bosch).



width down to tenths of a millimeter.This allows non-conforming (i.e. un-closed) capsules to be rejected beforethey reach the good capsule contai-ner or downstream equipment,where they can cause problems inthe blister packaging process, for in-stance. As an example, the capsule inImage 12 is approximately 1 mm lon-ger than the capsules in Images 11and 13, because it was not comple-tely closed. By measuring the widthof the capsules, it can be determinedif they have damage to their sidewalls or if they are deformed. When

examining capsule quality, the con-sistency of the capsule fill should alsobe considered. This can provide in-sight into the current performance orilluminate any possible problemswith the powder station. The opera-tor of the machine can see the con-dition of the powder plugs within theclosed capsule and can thereby de-termine if the plug is completely,partly, or not at all disaggregated.In Image 14 the individual tampinglayers are even easily distinguishable.When considering the steadily in-creasing PAT needs of pharmaceuti-

cal production, the x-ray system hasenourmous potential. With the helpof the digital image evaluation soft-ware, process-relevant informationbeyond the 100 % on-line weight con-trol function can be automaticallyobtained and evaluated. The furtherdevelopment of the x-ray system willtake place in conjunction with thepharmacueutical industry to deter-mine which image-evaluation appli-cations make the most sense for thedeveloping needs of the industry.

Image 12:Pellet Fill Me-dium Fill Le-vel (Source:Bosch).

Image 15: NoPowder Plug(LoosePowder) (So-urce: Bosch).

Image 16:GoodPowder Plug(PartiallyDisaggrega-ted) (Source:Bosch).

Image 11:Pellet FillHigh Fill Le-vel (Source:Bosch).

Image 13:Pellet Fill LowFill Level(Source:Bosch).

Image14: Indivi-dual Tam-ping LayersDistinguis-hable (Sour-ce: Bosch).

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Documents

100 %On-lineQualityControlwith X-Ray-Technology · 2012. 7. 19. · tem in the capsule filling machine is executed semi-automatically. After the fully-automatic sensor calibrati-on,