Fundamentals and Challenges of

Fundamentals and Challenges of Pharmaceutical Containment Applications

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.

Why Containment and/or High Containment?

• „50% of all new APIs must beclassified as products with high potent active ingredients (HPAPIs).“

Source: IMS, 2015

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).

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

Handling HPAPIs – Where is the issue?

- Visually HPAPIs cannot be distinguished from harmless additives

- Real-time measurement methods do not not exist

Lactose HPAPI

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)

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



Environment


ExposureMeasurement


HPAPI

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

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



Environment


ExposureMeasurement


HPAPI

What has to be kept in mind?

Containment

Physical Safety

ATEX

GMP

TabletingProcessPowder Tablet

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

Physical Safety- Basis: machine directive 2006/42/EG

- Software „SafeExpert“

- Guided, risk-based evaluation of all technical

aspects

- Overall-CE applied for customer

projects

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]

Containment: Target Value Exposure Measurement?

Containment: Interactions – Human / Machine

• Bad design leads to containment risks

• Fette Compacting:

Standard machine series, therefore

optimized technology and no try-and-

error

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

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



Environment


ExposureMeasurement


HPAPI

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.

Measuring principle SMEPAC

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

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

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

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

eco

mp

lete

rep

etit

ion

s(R

un

s)

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

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.

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


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

Why is no OEB specific technology available ?

1,000 – 5,000

100 – 1,000

10 – 100

1 – 10

<1

<0.2

1 Nontoxic


3 Slightly toxic

4 Toxic

5 Highly toxic

6 Extremely toxic

OEB OEL [µg/m3]

CG-Measurement: 5 µg/m³

Why is no OEB specific technology available ?

1,000 – 5,000

100 – 1,000

10 – 100

1 – 10

<1

<0.2

1 Nontoxic


3 Slightly toxic

4 Toxic

5 Highly toxic

6 Extremely toxic

OEB OEL [µg/m3]

CG-Measurement: <0,2 µg/m³

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

Fundamentals and Challenges of

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