Crystal - Business Review Webinars

Crystal , 

the Closed Vial Technology 

SAFER and EASIER Aseptic Filling 

Business Review Webinar 

September 28, 2011 

Confidential | Copyright © 2011 | Aseptic Technologies | All rights reserved

Key messages on Crystal ® Technology 

•Consists of two elements: 

–A ready to fill vial 

–A filling line piercing and re-sealing the 

stopper 

Crystal 

Technology 

•Has been fully validated for filling of aseptic 

drugs 

•Offers key advantages: 

–Safer for the patient 

–Easier for the manufacturer 


Aseptic filling: a complex process… 

GLASS VIAL FILLING 

vials 

stoppers 


… still risky for the patient 

Infections by contaminated drugs: 200,000 

infections per year (1/100,000 injections) 

Reduction of exposure to preservatives 

As a precautionary measure, the Public Health Service (FDA, NIH, CDC, 

HRSA) and the American Academy of Pediatrics issued two Joint 

Statements, urging vaccine manufacturers to reduce or eliminate 

thimerosal in vaccines as soon as possible (CDC 1999) and (CDC 2000). 


Challenges of Aseptic Technologies 

Aseptic filling is currently 

How to make it 

Still risky 

SAFER? 

More and more complex 

EASIER? 


New concept of Crystal ® | Process 

Molding site 

Irradiation unit 

Molding & Closing 

(ISO 5) 

Assembly 

(ISO 8) 

Sterilization 

(Gamma irradiation) 

Pharmaceutical site 

Filling line under barrier (ISO 5) 

Clean & sterile 

“ready to fill” 

vial 

Capping Laser re-sealing Filling 


Vial manufacturing process 


Closed vial filling line operations 


Six formats of vial available 

1 ml 2 ml 6 ml 10 ml 20 ml 50 ml 


Two formats of Laboratory lines 

Crystal M1 

Filling 

Station 

• Independent tools with manual 

operations 

• To be installed in existing environment 

• Designed to fill very small batch filling 

(

Three formats of Production lines 

Crystal Cx 

Filling line 

• Designed to fill medium scale 

commercial batches 

• Capacity: up to 75 vials/min* 

• Space needed: 40 m² (footprint: 9 m²) 

Crystal PX 

Filling line 

• Designed to fill commercial batches 

• Capacity: currently up to 150 

vials/min*, is expected to be increased 

• Space needed: 60 m² (footprint: 16 m²) 

Crystal Pxx 

Filling line 

• Designed to fill large commercial 

batches 

• Capacity: up to 600 vials/min* 

• Space needed: 100 m² (footprint: 44 

m²) 

* 1 ml vials 

• Capacity increase is feasible by adding 

filling heads and lasers 


Status of the 

Technology 


Status of product testing 

83 products filled in Crystal vial 

• Various categories tested, including 

– 56 biological products (vaccines, antibodies, proteins, cells, viruses, 

mRNA,…) 

– 7 cytotoxic products 

– 7 lyophilized products 

• 46 different companies, including 

– 4 top 10 pharma 

– 4 top 10 biotechs 

• Currently 73 results obtained 

– 27 products with better stability than with other containers 

– 9 products with lack of stability* 

– 39 products with good stability 

* 3 are unstable in glass as well, one unbuffered product was sensitive to acid, two are 

degraded due to oxygen ingress without protective packaging, one is hydrophobic, one is 

more absorbed than in PP but less than in glass and one is adsorbed 


Users of Crystal equipment worldwide 

Active users 

Equipment to be delivered 

* Projects not indicated are confidential 


First product approved 

• Product filled in late 2007 in AT facility (filling line in CVFS, 

located in ISO8 clean room) 

• Two years of stability obtained in early 2010, all data within 

specifications 

• Data submitted to EMA in January 2011, CHMP recommended 

approval in May 2011 with sentences such as “…very 

interesting innovative technique…”, approval granted by EMA 

in July 2011 


They talk about us ... 

“Certain modern manufacturing designs (isolators 1 and 

"closed vial" filling) afford isolation of the aseptic process 

from microbiological contamination risks (e.g., operators and 

surrounding room environment) throughout processing.” 

1 This does not apply to RABS (Restricted Access Barrier Systems) 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm 

"Can the Closed Vial filling equipment be surrounded by 

Grade C environment? I would say "Yes" because the vials 

are permanently closed" 

Personal opinion from Dr. Jean-Denis Mallet (Former Head of the Pharmaceutical, API and 

Cosmetics Inspection Department at the French Health Products Regulatory Agency 

(AFSSAPS) ) expressed at European Compliance Academy, Dusseldorf, March 10, 2010 

Simply Safer ! 


Major Advantages 

SAFER 

+ 

EASIER 


Some important vial properties 

Anticounterfeiting 

possibilities 

Large piercing area 

secured by V- 

pressure rib 

No silicone, 

very limited 

leachables 

Resistant to 

damages 

Closed 

container 

V-pressure rib, 

suitable for very 

low temperature 

storage 

Stopper designed 

to minimize 

residual volume of 

liquid 

Vial = isolator at item level 


Key advantages of Crystal ® Technology 

SAFER 

EASIER 

INCREASE 

PROFIT 

For whom? 

• For your regulatory 

team 

• For your supply chain 

team 

• For your 

manufacturing team 

• For your QA/QC team 

• For your marketing 

team 

• For your financial team 

• For your 


• For your sales team 

Why? 

• Provide a top-class sterility assurance 

level thanks to a closed ready to fill 

container 

• Secure the products inside an 

unbreakable and coded container 

• Simplify entire filling process (lean 

manufacturing) 

• Reduce initial and regular validation 

work 

• Facilitate handle by healthcare 

specialists 

• Reduce capital expenses 

• Reduce operating expenses 

despite vials more expensive than 

unclean non-sterile glass vials 

• Boost sales thanks to better perception 

by end-users 



SAFER 

EASIER 

INCREASE 

PROFIT 

For whom? 


team 


team 

• For your 




team 


• For your 



Why? 



container 






work 


specialists 






by end-users 


Impact of open glass vials and inappropriate materials 

FDA identified steel, rubber and fiber particles in vials filled at 

Genzyme Allston site 

Despite that Genzyme claimed that vials with particles are 

identified and eliminated, the FDA decided to: 

• Refuse approval for manufacturing of Lumizyme 

• Recommend close inspection by healthcare practitioners for 5 

drugs including Cerezyme and Fabrazyme 

Amgen identified flakes of glass in EPO vials due to ageing 

Amgen and J&J withdrew respectively 200 and 155 lots from the 

market 

Shelf-life has been reduced from 36 to 12 months 

Hospira identified metal particles in Liposyn and Propofol vials 

Hospira withdrew 85 lots of Liposyn and 73 lots of Propofol from 

the market 


Exposure to environment 

From hot-air tunnel up 

to stoppering 

> 30 minutes in most 

cases 

From loading up to stoppering, 

critical surface in direct 

contact with bowl and ramps 

From few minutes up to hours 

Exposed all along the 

process but no contact 

Never open 

except during 

piercing 

Exposed all along the 

process and in contact 

with stopper surface 

Wiped during entry 

inside vial 


Exposure risks 

Contaminated containers per million if 1 cfu every 1000 m³ 

Glass vial 

30.7 

Open ampoule 

Prefilled syringe 

5.5 

8.1 

Crystal vial 

Blow-fill-seal 

0.20 

0.12 

Risk of contamination is reduced 

~150 times compared to classical 

glass vial 

Grade A = < 1 cfu/m³ 


Particles comparison between glass vial and closed vial 

Vials having faced full filling and collection process 

Number of particles 

Closed vial in CVFL 

Glass vial in isolator 

Particles ≥5 µm 



600 

60 

6 

500 

428 

50 

47 

5 

400 

40 

4 

300 

237 

30 

23 

3 

200 

20 

2 

100 

10 

1 

1 

1 

0 

0 

Particles reduced by a factor 2 

compared to glass vials filled in isolator 

0 


Leachables | Crystal ® Closed Vial 

Leachables in WFI* 

Range 

From 10 ppm to 50 ppm 



Less than 1 ppm 

T = 24 months 

Acetic acid 

Formic acid 

t-butanol 

Very few products. No concern 

with toxicity and carcigenocity 

Crystal ® vials are also 

- latex free 

- silicone free 

Very few leachables. 

No toxicity concern, according to FDA recommended expert 

* Similar results obtained in ethanol 10%, PBS, NaCl 0.9% and 2-phenoxyethanol 0.5% 


Typical leachables from other containers 

2-methylpentane 

3-methylpentane 

Hexane (class 2 solvent*) 

Methylcyclopentane 

Cyclohexane (Class 2 solvent*) 

Butylated Hydroxytoluene (BHT) 

Lauric acid 

Palmitic acid 

Myristic acid 

Stearic acid 

Aliphatic alcohols (Class 3 solvent*) 

Dibutylamine (10-50ppm, Permitted 

Daily Dose for infant is 11 µg) 

Metal ions including 

Barium 

Arsenic 

Alkali compounds 

Flakes of glass due to 

product aggression 

Silicon oil 

Tungstene 

Vulcanizing agents 

Glass components as for 

vials 

High surface/volume ratio 

increasing risk 

* According to ICH Q3C guideline : class 1 = highly toxic solvent, class 2 = toxicity proven 

at low dose, class 3 = toxicity at higher dose. 

Sources: Biopharm International (April 2010), J Radioanal. Nucl. Chem. (2004), 

AAPS (2007), Drug Safety Institute, J Pharm. Sc. (1986) 



SAFER 

EASIER 

INCREASE 

PROFIT 

For whom? 


team 


team 

• For your 




team 


• For your 



Why? 



container 






work 


specialists 






by end-users 


Drop test 

Results with 10 ml vials 

(filled with 10 ml mannitol 15%) 

120 

% of vials 

100 

Crystal vials 

without visual 

product leak 

80 

60 

40 


without damage 

Glass vial after 

50 cm drop 

20 

0 

Non exploded 

glass vials 

0 1 2 3 4 5 

• At table height: ~1/2 glass vial are broken 

• At chest height: almost all glass vials are broken 

• Crystal vials are still intact at 2 meter height 

Meter for drop test 

• In case of damage, usually Crystal vial does not spread the product 


Drop test 

Results with small vials 

(2R glass vial and 1ml Crystal vial, filled with 1 ml mannitol 15%) 

120 

% of vials 

100 

80 


without damage 

60 

40 

20 

0 

Non exploded 

glass vials 

0 1 2 3 4 5 10 6 

• At table height: risk of glass vial breakage is 

present 

• Crystal vials are still intact over 10 meter height 

Meter for drop test 


Freeze-thawing 

Results after freezing at -70°C and thawing at RT 

(filled with mannitol 15%) 

% of intact 

vials 

120 

100 

80 

5 ml glass 

vials* 

All format of Crystal 

vials (5, 10 and 20 ml) 

60 

40 

10 ml glass 

vials* 


under thawing 

process 

20 

0 

20 ml glass vials* 

0 20 40 60 80 100 

% nominal volume filled 

• Crystal vials are very resistant to product expansion, 

but not glass vials 

• Bigger is the glass vial, more fragile it is 

* published data: Jiang et al., PDA J. Pharm. Sc. And Technol., 61, 441-451 (2007) 


Secured traceability and anti-counterfeiting 

Examples of secured coding technologies 

On-line coding of RFID 

secured under the cap 

On-line laser coding on top ring 

Alpha 

numeric 

2D matrix 

Fully secured vial 

through on-line coding 



SAFER 

EASIER 

INCREASE 

PROFIT 

For whom? 


team 


team 

• For your 




team 


• For your 



Why? 



container 






work 


specialists 






by end-users 


Process simplification 

GLASS VIAL FILLING 

vials 

stoppers 

Crystal ® FILLING 

Lean 

manufacturing 



SAFER 

EASIER 

INCREASE 

PROFIT 

For whom? 


team 


team 

• For your 




team 


• For your 



Why? 



container 






work 


specialists 






by end-users 


Market research results Crystal ® vs. glass vials 

Crystal preferred No preference Glass preferred 

• 246 healthcare professionals from hospital settings interviewed 

• 71 doctors, 161 nurses and 14 hospital pharmacists 

• 134 in Europe (F, B) and 110 in the US (West and East Coasts) 

87% of professionals prefer Crystal ® 

87 6 7 

In each region 

By each professional 

Europe 

USA 

89 

6 5 

85 5 10 

Doctors 

Nurses 

Pharm. 

90 

85 

86 

4 6 

6 9 

14 

Full presentation available on request 


Preference drivers 

•87% of professionals expressed a preference for 

Crystal 

•What are the drivers of this preference? 

Easy to handle 

45 

Shock-resistance 

36 

Easy to open 

Asepsis improvement 

Easy to pierce 

Easier in general 

26 

23 

21 

18 

Vial stability 

11 

Secured marking 

4 

“Delivery systems that score high with end-users may provide a 

competitive edge as pharmaceutical companies start sharpening their 

life cycle management tools” M. Romacker, Amgen Inc. 

Full presentation available on request 



SAFER 

EASIER 

INCREASE 

PROFIT 

For whom? 


team 


team 

• For your 




team 


• For your 



Why? 



container 






work 


specialists 






by end-users 


Cost savings using the closed vial 

Capital expenses 

Vials 

API 

Filling line 

Total cost 

of filled vial 

Operating expenses 


Reduction of API expenses 

Residual 

volume = 12 µl 

Residual 

Volume = 3 µl 

Difference = 9µl 

0.09 USD saving per vial 

if API price is 10 USD/ml 

Crystal ® vial stopper specially designed to ease 

liquid collection and to reduce API expenses 


Conclusions 


Closed vial characteristics 

•The Closed Vial technology provides a safer solution 

to the patient 

•The Closed Vial technology simplify the entire filling 

process 

•The regulatory authorities have well understood the 

advantages of this technology compared to classical 

ones 

Simply Safer !

Crystal - Business Review Webinars

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