Fundamentals and Challenges of
Transcript of Fundamentals and Challenges of
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Fundamentals and Challenges of Pharmaceutical Containment Applications
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Goal Fette Compacting Containment Guard
A comparable and reliable technology and measuring method which
enables the customer to make a decisions when
considering containment solutions, already in the
planning stage.
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Why Containment and/or High Containment?
• „50% of all new APIs must beclassified as products with high potent active ingredients (HPAPIs).“
Source: IMS, 2015
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Definition HPAPIs
• Pharmaceutical ingredient with a potency limitation of 150µg/kg body weight or less
• Pharmaceutical ingredient with a permitted room air concentration of (OEL) 10 µg/m³ based on 8 hour average value
• Pharmaceutical ingredient which in little dosages is considered potentially carcinogenic ormutagenic, damages the embryological development or causes mutations.
Source: A.W. Ader et. al, Chem. Today 25 (2), 56–60 (2007).
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HPAPIs – Where is the issue?
- Common limits are in the range from 10µg/m³ to 0,1 µg/m³
0,1µg = 0,0001 mg = 0,0000001 g
- This magnitude intangible with usual measures
- Example „shipping container“:
- sugar cube of 3 g
- 40‘-Container capacity = 67,5 m³
- for a concentration of 10 µg/m³ the sugar cube must
be distributed equially to 4444 containers to undercut
the limit
Freighter „Colombo Express“, Source: Wikipedia, Hummelhummel
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Handling HPAPIs – Where is the issue?
- Visually HPAPIs cannot be distinguished from harmless additives
- Real-time measurement methods do not not exist
Lactose HPAPI
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1,000 – 5,000
100 – 1,000
10 – 100
1 – 10
<1
<0.2
1 Nontoxic
2 Practically nontoxic
3 Slightly toxic
4 Toxic
5 Highly toxic
6 Extremely toxic
OEB OEL [µg/m3]
OEB vs. OEL vs CPT (Containment Performance Target)
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Influencing factors for contamination control (technical point of view)
Defintion of health based limits(OEL, PDE)
Definition of ProcessEquipment and
Environment
Conduct ofContainment
ExposureMeasurement
Goal: safe andefficient processing of
HPAPI
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Defintion of health based limits(OEL, PDE)
Definition of ProcessEquipment and
Environment
Conduct ofContainment
ExposureMeasurement
Goal: safe andefficient processing of
HPAPI
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Specification of active ingredient limits− Specification of active ingredient limits are different based on objectives (GMP/operator
protection)
− Calculation performed by occupational medicine based on animal and/or patient testing
OEL Occupational Exposure Limit
NO(A)EL No Observable (Adverse) Effect Level
PDE Permitted Daily Expsoure
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Specification of active ingredient limits: Operator protection
- Risk of exposure at workplace (air/skin)
- Active ingredient limit is Occupational Exposure Limit (OEL),
which is the concentration of the active ingredient in the room
air, measured (usually) as average value of a 8 hour shift
- Based on EMA, OSHA, HSE etc.
- EMA: Implementation of Health Based Exposure Limits
Source: EMA/CHMP/CVMP/SWP/169430/2012, www.ema.europa.eu
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Defintion of health based limits(OEL, PDE)
Definition of ProcessEquipment and
Environment
Conduct ofContainment
ExposureMeasurement
Goal: safe andefficient processing of
HPAPI
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What has to be kept in mind?
Containment
Physical Safety
ATEX
GMP
TabletingProcessPowder Tablet
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Process and GMP- Definition of system boundaries
- Selection of process components based
on required output, tablet properties
- Selection of software modules and
process equipment, in-process control
based on GMP requirements
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Physical Safety- Basis: machine directive 2006/42/EG
- Software „SafeExpert“
- Guided, risk-based evaluation of all technical
aspects
- Overall-CE applied for customer
projects
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Selection of Process Equipment based on Containment-Requirements
Containment Limit
Containment Performance
Pharma Manufacturer
Machine Manufacturer
- Active ingredient characteristics- Limit defined as OEL [µg/m³] with
active ingredient content or as Containment Performance Target (CPT)
- Machine characteristics- Measurement according to
SMEPAC
[µg/
m³]
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Containment: Target Value Exposure Measurement?
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Containment: Interactions – Human / Machine
• Bad design leads to containment risks
• Fette Compacting:
Standard machine series, therefore
optimized technology and no try-and-
error
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Containment: Safety Layer •Layer 1
- Physical barrier
- Covers main part of protective function
- Process intervention through glove ports possible
•Layer 2
- Negative pressure within the whole tableting system
- Containment system is robust in case of operating errors,
leakage, etc.
Source: EN ISO 14644-4:2001, figure A.5
Source: EN ISO 14644-4:2001, figure A.7
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Containment: Safety Layer •Layer 3
- Control of air flow / negative pressure via
Fette Compacting Airmanagement
- Robust reaction in response to critical system
conditions
- Power failure
- Malfunction filter system
- Overpressure in process system
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Defintion of health based limits(OEL, PDE)
Definition of ProcessEquipment and
Environment
Conduct ofContainment
ExposureMeasurement
Goal: safe andefficient processing of
HPAPI
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Basis of Measurement: ISPE Guideline
Source: ISPE, 2017
• Past: Standardized Measurement of Equipment Particulate
Containment (SMEPAC)
• Today: APCPPE, abbr.: SMEPAC
• Good description of measuring sensors, analytics, surrogate
selection
• No process specific descriptions, which means operating status,
sample positions etc.
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Measuring principle SMEPAC
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Selection of Surrogates- Crucial factors are the processability of the active
ingredient and the traceability in the lab
- Indicated is the minimum quantity that can be
proved on a filter disc by means of HPLC (LOD)
- Challenge in tableting: pure substances according
to SMEPAC are hardly compactable!
•
Source: Petroka, ISPE 2010
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Demand of detailing SMEPAC- SMEPAC defines the framework, but five teams still could reach five different conclusions when
measuring a tablet press!
- Goal Fette Compacting:
A comparable and reliable measuring method which
enables the customer to make sound decisions when
considering containment solutions, already in the
planning stage.
- Solution: Evaluation according to
Containment-Guard procedure
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Containment Guard•The Containment Guard is the measuring method and the related test seal of Fette Compacting GmbH for the
technical retention performance.
Parameter predefined? SMEPAC Containment Guard
Sampling Method Yes Reference to SMEPAC
Test Substance Multiple Options Reference to SMEPAC
Data interpretation Multiple Options Reference to SMEPAC
Probe Positions - Yes
Operator Position - Yes
Tablet press parameters - Yes
Operating Modes incl. Error tests
- Yes
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Measurement according to Containment Guard Standard
CycleNo.
Name of Measurement Description Duration per Cycle
1 Background Level Yes 60 min
2 Production Run Normal operation mode 45 min
3 RTP Transfer In-Bound and Out-Bound transfer through RTP 30 min
4 Error test: Power failure Disconnect power from Filter and Tablet press 30 min
5 Cleaning of Compression Chamber
With closed window flaps, e.g. vacuum (and WIP)
60 min
6 Disconnect peripheral devices If applicable 30 min
7 Removal of Filling Station One window flap open, manual removal 60 min Thre
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Conducting SMEPAC•- Measured value acquisition and evaluation by accredited
test laboratory
- Standard procedure „Containment Guard“
- defined sampling positions
- defined operating parameters
- Consideration of error scenarios
→ Comparable Containment Performance
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Summary- Succesful contamination control depends on used active ingredient, used equipment
and correct handling of both.
- The control of all risks and interactions between room, equipment and operators is
joint task of all experts – hence contact us early in the project phase.
- With the Containment Guard Fette offers a standard method to evaluate the
retention performance of tableting presses which further ensures comparability of
the equipment and a safe project planning.
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How we come to the Containment to the needs?
1,000 – 5,000
100 – 1,000
10 – 100
1 – 10
<1
<0.2
1 Nontoxic
2 Practically nontoxic
3 Slightly toxic
4 Toxic
5 Highly toxic
6 Extremely toxic
OEB OEL [µg/m3]
Keep in mind each OEB has a power of ten!
CPT [µg/m³]is the most important value for us!
OEL [µg/m³]of HPAPI and drug load in %
or
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Why is no OEB specific technology available ?
1,000 – 5,000
100 – 1,000
10 – 100
1 – 10
<1
<0.2
1 Nontoxic
2 Practically nontoxic
3 Slightly toxic
4 Toxic
5 Highly toxic
6 Extremely toxic
OEB OEL [µg/m3]
CG-Measurement: 5 µg/m³
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Why is no OEB specific technology available ?
1,000 – 5,000
100 – 1,000
10 – 100
1 – 10
<1
<0.2
1 Nontoxic
2 Practically nontoxic
3 Slightly toxic
4 Toxic
5 Highly toxic
6 Extremely toxic
OEB OEL [µg/m3]
CG-Measurement: 5 µg/m³
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Why is no OEB specific technology available ?
1,000 – 5,000
100 – 1,000
10 – 100
1 – 10
<1
<0.2
1 Nontoxic
2 Practically nontoxic
3 Slightly toxic
4 Toxic
5 Highly toxic
6 Extremely toxic
OEB OEL [µg/m3]
CG-Measurement: <0,2 µg/m³
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The F10i Containment is the perfect machine for active substances
• Containment solution to the needleads to a technology at an affordable budget
• Less complexity
• No contact with active products
• Dusttight press room within the machine
• Fail-safe machine operation and control
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