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URo 06/27/2016 Page 1

Responsibilities
► Manage BINDER Subsidiary for Sales and Service
in North, Central and South America
► 12 Years with BINDER
► 25 years in the Instrument & Equipment Industry
► Located in New York, USA
Uwe Ross
President BINDER Inc.
Phone: +1 631 224 4340 x 112
Email: uross@binder-world.com Experience
► Research and Development Engineer
► Product Manager
Education
► Business Development Manager
► German Air Force Academy Graduate
► Marketing Director
► BSEE Electrical Engineering
► Divisional Vice President
► MSEE Information Technology

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ICH Guidelines

Stability Test - Product Selection

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Abbreviations

ICH International Conference on Harmonization


API Active Pharmaceutical Ingredient Guideline
FPP Finished Pharmaceutical Product

DQ Design Qualification
IQ Installation Qualification Equipment
OQ Operating Qualification Validation
PQ Process Qualification

GCP Good Clinical Practices


GMP Good Manufacturing Practices Process
GLP Good Laboratory Practices

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GLP, GCP, GMP activities during pharma development

Preclinical Clinical Phases


API Discovery Commercialization
Development I - III

Not regulated GLP GCP GMP

+
GMP
+
GMP

Degree of GMP compliance

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Schematic of stability testing

3 Scale- 4 5
1 API 2 Pre- 6 On-
up batch Registration Follow
discovery formulation
batch going
-up
Pre-clinical:
Step 1 Stress test with the API at temperatures from 25°C to 70°C relative humidity up to 75% up to 3 months
(Is the active Ingredient temperature and humidity stable?)

Step 2 Different tests with API and excipients

Step 3 Stress tests with one or more batches to determine expiration date, storage conditions and
parameter for long term testing
(Determine packaging, storage and shelf life!)

Clinical:
Step 4 Long term and accelerated testing of 3 production scale batches  API and FPP duration up to 12
month
(Long Term Test of different batches!)

Commercialization:
Step 5 Stability tests of 3 production batches of API and FPP duration up to 60 month

Step 6 Annual Stability tests with the API and FPP


(Ongoing Quality Control / Batch Control!)

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ICH Publications on Stability

 Q1A (R2) Stability testing of new drug substances and products


– Parental Guideline
 Q1B Stability testing: Photostability testing of new drug substances and products
– Annex to Q1A(R2) Describes standard conditions for photostability testing

 Q1C Stability testing for new dosage forms


– Annex to Q1A(R2)

 Q1D Bracketing and matrixing designs for stability testing of new drug substances
and products
– Annex to Q1A(R2) Guidance on reducing the amount of testing
► Q1E Evaluation of stability data
Annex to Q1A(R2)
 Q1F Stability data package for registration applications in climatic zones III and IV
Withdrawn by ICH  Replaced by WHO guideline on stability testing

 Q5C Stability testing of biotechnological/ biological products


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Scope of Stability Testing

 Stability testing is performed throughout the complete development


process

 Scope of stability testing is to determine

– the expiration date of the pharmaceutical product ( FPP )


– the re-test period of the pharmaceutical substance ( API )
– the correct packaging (marketing containment)

– if API or FPP changes under the influence of



– Temperature, Humidity and Light in a defined Time interval

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Q1A (R2) Stability Testing Range - Formal Stability Studies

Study Minimal General Use Refrigerator Freezer


Duration
Long term 12 months 25 °C ± 2 °C – 60% RH ± 5% RH 5 °C ± 3 °C (no - 20 °C ± 5 °C
or humidity control)
30 °C ± 2 °C – 65% RH ± 5% RH
Accelerated 6 months 40 °C ± 2 °C – 75% RH ± 5% RH 25 °C ± 2 °C -
60% RH ± 5% RH
Intermediate* 6 months 30 °C ± 2 °C – 65% RH ± 5% RH - -

Stability tests for aqueous-based FPP packaged in semi-permeable containers


Study Minimal Duration General Use
Long term 12 months 25 °C ± 2 °C – 40% RH ± 5% RH ×
or
30 °C ± 2 °C – 35% RH ± 5% RH ◘
Accelerated 6 months 40 °C ± 2 °C – ≤ 25% RH ○
Intermediate* 6 months 30 °C ± 2 °C – 65 %RH ± 5% RH
*If long term studies are performed at 25°C and the corresponding humidity
and if accelerated studies show significant changes then:
 An intermediate study has to be performed for subsequent assessment
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Product Specification

 Complete List of all Temperature and humidity specifications


×
Temperature Tolerance Humidity Tolerance ×
[°C] [±°C] [% RH] [% RH] ×
25 2 60 5
30 2 65 5
40 2 75 5
×
5 3 - - ◘
25 2 40 5

30 2 35 5
40 2 < 25 -

BINDER
KBF P 720

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Photostability Testing according to Q1B

Option 1 specifies one light source


 Artificial daylight fluorescent lamp combining visible
and ultraviolet (UV) outputs
 Refers to ISO 10977 (1993)

Option 2 specifies two light sources


 Cool white fluorescent and near ultraviolet lamp
 Near UV fluorescent lamp with a spectral distribution
from 320 nm to 400 nm

For confirmatory studies applying to Option1 or Option 2:


 Overall illumination of not less than 1.2 million lux hours
 Near ultraviolet energy of at least 200 watt hours/square meter
 Validated chemical actinometric system to ensure the specified light
exposure
 Specifies the use of calibrated radiometers/lux meters

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Validation / Qualification schematic

Validation Master Plan Documented evidence that the


device delivers continously
results acc. to URS

GXP User
Requirements Requirements Procedural Testing PQ
Specification URS

DQ Documented Verification of
Vendor Selection
Staff Training
SOPs
Functional Requirement
Specification FRS Documented Maintenance Plan

Design Specification DS Documented Verification of OQ


Calibration

IQ Documented Verification of Documented Verification of


Identification / Installation Operational Testing

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 What does this all translate to?

– Get the desired result?

– Get the desired result and be able to reproduce it!!

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Selection of the right product

How do I decide what to buy?

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Temperature Range and Ambient

5 °C above ambient 70 °C

Range
Make sure you stay away from temperatures too close to ambient [typical ambient is between 18º C and 32º C]

 ‘X’ above ambient => there is no refrigeration!


 To reliably hold 25 °C => heating and refrigeration is required

 Consider: How to provide an acceptable ambient temperature?


Not just during work hours!

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Temperature Tolerance

 The tolerance specification is the combination of:


– Uniformity
also called Variation
Temperature Tolerance in Space
@ time x

– Fluctuation
Temperature Tolerance over Time
@ Mid Chamber Location

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Uniformity

 Significant Effects on Uniformity:


• Chamber construction / Heat Source / Insulation
Tubular Heat in Air Jacket

Direct Heat

Tubular Heat in Double Air Jacket


APTLine – BINDER patent

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Uniformity

 Significant Effects on Uniformity (Variation):


• Manufacturing tolerances
• Ambient temperature

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Uniformity

 Significant effects on Uniformity:


• Airflow

? !

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Airflow and Uniformity
Product 1 Product 2 Product BINDER

Temperature range Temperature range Temperature range


5°C to 70°C 0°C to 60°C 0 to 70°C
*without lights *without lights without lights
*

Temperature uniformity Temperature uniformity Temperature uniformity


± 0.3°C ± 0.3°C at 25°to 37°C ± 0.2°C
(≤ ± 0.5°C at all other
temperatures)
Humidity uniformity Humidity uniformity Humidity uniformity
± 3%r.H. ± 5%r.H. ± 1.5%r.H.

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Humidity and Condensation

 Sources for the Water

 Humidity Generation
• Water Bath
• Spray
• Steam Generator
• Pressurized Steam Generator

 When does Condensation Occur?


 Where does Condensation Occur?

 Water Disposal
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Humidity Source

 Sources for the Water

Tap Water House Water No Water

Consider:
• Consistent Water Quality
• Sediments and impurities
• Pressure
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Humidity Generation

 Humidity Generation

Water Pan Spray Steam

Temperature Effect rise drop neutral

Reaction Time slow medium fast

Vapor Uniformity good low good

Contamination Risk exists exists boiled water

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Humidity Recovery Time

 Recovery Time (fast reaction time)


• Pressurized Steam Generator

What happens after the door is


opened and closed again?

Example:
BINDER KBF 720 Product C
+ 25°C / 60 % RH 2 min 15 min
+ 40°C / 75% RH 6 min 48 min

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Condensation

 When does Condensation Occur?


 Where does Condensation Occur?

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Dew Point

► The 100 % RH curve represents the saturated moist air


► This is equal to dew point temperature curve
► Example : Moist air at 35 °C with 50 % RH
is cooled down below the dew point temperature of 22 °C => Condensation occurs

Liquid

Dew point

Vapor

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Cold Spot

Forced condensation location out of harms way

Large evaporator for


cooling

Small evaporator for


dehumidification

Coldest region in the chamber

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Water Management

 Water Management:
• Management means:
Humidity that does not change the temperature in chamber and
everything taken care of from intake to drain

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Temperature Humidity Chart

 Temperature Range and Humidity Range are not independent!

Consider:
Condensation can be hidden in the
product specification

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Light Source Location

Can be installed right


above shelf

Light Cassette
Door Light Wall Light
Uniformity and Intensity
changes from front of
shelf to back or from
one side to the other

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Artificial Daylight

To achieve the specified light spectrum two different light bulbs are required

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Light Uniformity

Light cassette with uniformity grid

Spectral and intensity


homogenization

11000 11000
10000 10000
9000 9000
8000 rear 8000 rear
7000 7000
6000 6000
5000 5000
4000 4000
3000 middle 3000 middle
2000 2000
1000 1000
0 0
1 2 1 2
3 front 3 front
4 5 4 5

0-1000 Standard
1000-2000 lights
2000-3000 3000-4000 0-1000 BINDER Q1B Synergy
1000-2000 Light
2000-3000 3000-4000
4000-5000 5000-6000 6000-7000 7000-8000 4000-5000 5000-6000 6000-7000 7000-8000
8000-9000 9000-10000 10000-11000 8000-9000 9000-10000 10000-11000

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Light Sensors

100% 100%

100%
70%

100% 0%

Spherical sensor measures true dosage Planar sensor measures a fraction of dosage

UV and visible light need separate sensors

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Additional Considerations

Refrigeration Source
Peltier Cooling

Compressor Cooling

Power Supply

Heat Dissipation

Computer Interface

Alarms

Accessories

Service

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Thank You!
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