|| equipment

How to set up a Project for

Handling High Potent Products
under Isolator
Case Study

Javier Alonso Gómez

Industrial Engineer. General Manager of Litek Pharma
Alex García
Mechanical Designer. R&D Engineering Department. Litek Pharma.
Gastón Ariel Estruch
Operations Director, Gentec Pharmaceutical Group, Pharmanoid HPAPI Site, and General Manager AppChem

The following article is a case study. We focus on the definition of different phases of a high potent product
handling project under isolator. The processes to be carried out in the isolator environment will be the weighing
of products, with exposure limits of 0,01 µg/m3. During the project, we will analyse the different phases that will
allow us to adequately assess the risks and select the appropriate mitigation mechanisms.

Keywords: Isolation, Containment, Drug production, Handling High Potent Products

El siguiente artículo es un caso de estudio. Nos enfocamos en la definición de las diferentes fases de un proyecto
de manejo de productos de alta potencia bajo aislador. Los procesos a realizar en el ambiente del aislador
serán el pesaje de productos, con límites de exposición de 0,01 µg/m3. Durante el proyecto analizaremos las
diferentes fases que nos permitirán evaluar adecuadamente los riesgos y seleccionar los mecanismos de mitigación
adecuados

Palabras clave: Aislamiento, Contención, Producción de fármacos, Manejo de productos de alta potencia

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INTRODUCTION
Containment in the use and handling
of high potent products has several
aspects that must be analysed before »» Another important point is to determine the
tackling a project with this type of
product. Containment is not absolute.
toxicity of the product to be handled. In many
The different levels of containment cases, a detailed characterisation of a product is
that can be obtained will depend on
not available
the system and technical solutions
that we apply. The different levels of
containment that can be obtained will
depend on the system and technical
solutions applied. The evaluation and
verification of the containment level
must be in accordance with the analysis
and detection capacity. 6. Mock-Up of the proposed solution. CASE STUDY
The development of new and more a. Ergonomics test. 1. User Requirements Analysis
active pharmaceuticals ingredients b. Material transfer tests. In this article we study a weighing
and with lower therapeutic doses, it c. Mock-up validation. case with the following starting data:
forces extreme containment measures 7. Equipment construction.
and ultimately also forces the use of 8. FAT testing. • API, characterised as
increasingly sophisticated analytical 9. Full Equipment Qualification. OEL=0.01µg/m3 and a containment
detection techniques. 1 0 . C o n t a i n m e n t Va l i d a t i o n level characterized OEB<0.01µg/m3.
A drug production project with a (SMEPAC) [3]. • Product in powder form. It’s
highly potent active ingredient requires
a detailed study, from concept to
validation. In this article we want FIGURE 1. Typical Risk Management Process [1]
to focus on the field of primary
containment that we can achieve with
a suitable design of the process under
isolator. In particular, we will analyse a
product weighing process.

PROJECT PHASES
It is important to carry out the analysis
of the project in phases and to do it in
an orderly manner to analyse all the
steps of the process, particularly in
this case a process of weighing a high
potent product.

1. User Requirements Analysis.

a. Product(s) to be weighed.
b. Characterisation of the
products.
c. Batch sizes to be weighed.
d. Number of batches per shift.
e. Product reception containers.
2. Risk Assessment.
3. Containment Strategy.
4. Conceptual design of containment
equipment.
5. Detailed Design of the containment
equipment.

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How to set up a Project for Handling High Potent Products under Isolator

uniform and powdery fine solid, is a These categories are set based on - Communication with Regulatory
non-crystalline and light powder that a detailed toxicological evaluation of Authorities.
is suspended generating clouds. all possible adverse effects. The final • Review and monitoring of process
• Source Container: Drum different determination of the product category risks.
dimensions. does not depend on a single factor, FMEA Analysis (Failure Mode Effects
• Weighing batches from 0.1 to 7 kg. such as the therapeutic dose. The Analysis) (Table 1 and 2)
• Closed containment system for categorization and the OEL must be
safe transfer to formulation reactor. carried out by an expert occupational 3. Containment strategy
toxicologist that will determine the The risk assessment concludes that
2. Risk Assessment level of containment necessary for a the containment level of the primary
Before initiating a risk analysis of this safe work with the product. barrier is such that it can only be
nature, it will be necessary to establish achieved using an isolator.
a basis for proper management • Planning. Detailed planning is In this phase, the laboratory must
(Figure 1). important, and adequate knowledge draft the URS document, with as much
From the human resources point of the personnel involved and their definition as possible. It is intended
of view, it is necessary to name a availability is also important. that this document should include the
person in charge, and to create a • Contents of the risk analysis: most important aspects of the isolator
multidisciplinary team to analyse and - Starting data. from the end-user’s perspective.
approach the assessment from all - Analysis, e.g., following FMEA Many of these aspects are covered
perspectives: (Failure Mode Effects Analysis) in the following conceptual and
In this case the project team would (Figure 2). detailed design points.
be formed by : - Conclusions document.
• Communication of RISKS: 4.Conceptual design of the
• Responsible: - Information Distribution Group. containment equipment
- Laboratory Engineering Manager.
• Other Resources:
FIGURE 2. FMEA method [4]
- Laboratory Production Manager.
- Laboratory Weighing Area Operator
- Laboratory HSE Manager.
- Advisor: Containment Expert and
Isolator Manufacturer
- Raw Material Supplier.

Detailed product characterisation

Another important point is to
determine the toxicity of the product
to be handled. In many cases, a
detailed characterisation of a product
is not available. In addition to the fact
that there is no universal and unique
system for categorising exposure
control bands, pharmaceutical
companies often define themselves
the values based on their knowledge
of the product itself, therapeutic
compounds, work environment,
equipment, controls, and other factors
[7,8].
A common example might be
Occupational Exposure Band (OEB 1)
(>1000 μg/m3), OEB 2 (10 to 1000 μg/
m3), OEB 3A (1 to 10 μg/m3), OEB 3B
(0.01 to 1 μg/m3), OEB 4 (<0.01 μg/
m3) [6].

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From a conceptual design point of • Filtration system through H-14 integrated, with a weighing scale
view, we propose an isolator with the Push-Push filters, and double H-14 suitable for the batch size and with
following characteristics (Figure 3): Push-Push extraction filters. No air the scale display easily accessible by
• Contaiment isolator, with Air Lock recirculation. the operator inside the isolator itself
for material transfer, with two gloves • The isolator must be airtight class preferably.
for handling loads, and main chamber 3 according to ISO 14644-7. • Manual cleaning with spray gun in
with 4 gloves, with integrated • The isolator chamber must be the air lock and spray balls and spray
weighing scale. welded, seamless, rounded, self- gun in the main chamber.
• Chamber and Air Lock with draining, and easy to clean. The • Control system with HMI, allowing
internal ISO 8 classification, turbulent internal roughness Ra<0.6. monitoring of the equipment and
flow, and door with inflatable seals. • A weighing system must be p ro c e s s e s , w i t h a n i n t e g r a t e d

CHART 1.
RESULTS OF THE RISK ASSESSMENT
RISK IDENTIFICATION RISK ANALYSIS RISK EVALUATION TOTAL RISK CONTROL STRATEGY

PRODUCT & PROCESS PERSPECTIVE

PRODUCT CHARACTERIZATION POTENTIAL RISK DETECTABILITY SEVERITY PROBABILITY RISK PRIORITY NUMBER RISK REDUCTION METHOD FINAL RISK COMMENTS
Product Toxicity OEL OEL <0,01µg/m3. Exposure during sampling/weighting 3 3 3 27 Use Isolator Accepted Exposure <0,01µg/m3
Number Batch per day - Value 2 Total Exposure Risk Time, per day. 2 2 2 8 Use Isolator Accepted
Batch Size - Value 0,5 to 7 kg Bigger batch, bigger risk. 2 2 2 8 Use Isolator Accepted
Product Pulverulence Product remaining floating in the air 3 3 3 27 Use Isolator Accepted
Explosive Index - ATEX , Ignition Sensibility Risk of explosion. 1 3 1 3 No ATEX clasification neccesary. Accepted Ignition Sensibility <0,2
<0,2
PRIMARY BARRIER: MATERIAL TRANSFER PERSPECTIVE

RAW MATERIAL PACKAGING POTENTIAL RISK DETECTABILITY SEVERITY PROBABILITY RISK PRIORITY NUMBER RISK REDUCTION METHOD COMMENTS
Drums Product loses during opening and close 2 3 2 12 Drum Docking System compatible Accepted Raw material supplyer have to
the containner. Diferent drum sizes. with diferent drums sizes. provide doble and continues bag
inside.
Cans with threaded cap. Product loses during opening and close 2 3 2 12 Use Air Lock chamber big enought, Accepted Only valid for small containers.
the containner and open the cans inside the
isolator.
Bottles, cans to transfer the product to Product loses during opening and close 3 3 2 18 Split Buterfly Valve or Single use foil Accepted Usefull for transfer the product
production. the containner transfer System with special to production.
connections.
PRIMARY BARRIER: HUMAN RESOURCES PERSPECTIVE

REGULAR PRODUCTION POTENTIAL RISK DETECTABILITY SEVERITY PROBABILITY RISK PRIORITY NUMBER RISK REDUCTION METHOD COMMENTS
Normal Operation Mistakes due to lack of trainning. 3 3 3 27 Training in HAPI sampling and Accepted
weighing, GMP, Containment. Use
of Mix Reality Technology.
Docking Systems and RTP Mistakes due to lack of trainning in 3 3 2 18 Trainning to use transfer systems, Accepted
transfer systems. docking systems and RTP
connectors.
Primary barrier use. Mistakes due to lack of training in 3 3 2 18 Training to use Isolators. Accepted
primary barriers and Containment
requirements.
PPE use. PPE selection, clothes, gloves, mask, 2 3 2 12 Trainning about PPE in containment Accepted
cap. Risk during gowning and evironment.
degowning during the entrance and exit
from containment area.
Exposure during the Degowning process. After an incident where an operator has 3 3 2 18 Mist shower before degowning. Accepted
been exposed to an abnormally large Emergency management training.
amount of product. Risk during
degowning.
PRIMARY BARRIER: CLEANING AND MAINTENANCE PERSPECTIVE

MAINTENANCE POTENTIAL RISK DETECTABILITY SEVERITY PROBABILITY RISK PRIORITY NUMBER RISK REDUCTION METHOD COMMENTS
Open Isolator Exposure of maintenance staff 3 3 3 27 Emergency management training, Accepted
and containment training.

Filter Change Exposure to the powders in the filters. 3 3 2 18 Use BI/BO filters. Accepted
Isolator Ventilation System Monitoring Lose tightness and containment, for any 2 3 2 12 Monitoring: pressure inside isolator, Accepted Including an Alarm management
technical reason. inflatable gasket status. Periodically system.
HEPA filters integrity test.
CLEANING PROCESS POTENTIAL RISK DETECTABILITY SEVERITY PROBABILITY RISK PRIORITY NUMBER RISK REDUCTION METHOD COMMENTS
Regular Cleaning Exposure of staff. Cross contamination. 3 3 3 27 Primary Barrier Cleanability, Accepted
roundes corners, drainability.
Cleaning Validation.
WIP & Spray Balls Insuficient cleaning posibilities, manual 3 3 3 27 Wet cleaning, manual and Accepted
process. semiautomatic cleaning process
with spray balls. Cleaning
Validation.
Waste Material Exposure during waste removal. 3 3 2 18 Safe waste material transfer. Accepted
Cotinues liner or disposable
betabag with RTP.
Waste Water Product loses through drain point, after 3 3 3 27 Connect drain point to a controled Accepted
WIP. drain network.
LITEK PHARMA - Containment Risk Assessment

CHART 2.
INTERPRETATION OF THE RPN

RISK PRIORITY NUMBER (RPN) PRIORITIES FOR ACTION AND DEDICATION OF RESOURCES
Priority and immediate action
19 < RPN < 27 : HIGH RISK
Maximum dedication of resources and information
Secondary action, through an action plan
9 < RPN < 18: MODERATE RISK
Less dedication of resources and information
Deferred action or not required
1 < RPN < 8: LOW RISK
Minimum dedication of resources and information

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How to set up a Project for Handling High Potent Products under Isolator

electronic data recording system FIGURE 3. Basic design, air lock and main chamber
validatable according to GAMP5.
• Integral alarm management
system for the isolator.
• Integration with the laboratory’s
MES system.

Material inlet/outlet ports:

• Inlet:
- Air Lock for infeed of materials
and tools of sufficient size. Two gloves
to allow for debagging tasks.
- DRUM elevator, prepared for
different sizes, and sealed with inflatable
gaskets during operation. FIGURE 4. 3D modelling of the proposed solution
• Outlet:
- Split Valve Port, to metal bag
or bottle.
- Waste Port, to continuous liner,
with inflatable gasket seal port port
or RTP.

At this stage, the FDS (Functional

Design Specification) document
must be drafted, which covers the
functional aspects of the isolator
design.

5. Detailed design of the

containment equipment
Regarding the detailed design,
we distinguish 5 main sections.
Mechanical Construction, Material
Transfer System, Cleaning System,
FIGURE 5. Drum loading at the base of the isolator
Control System, Ventilation and
Filtration System.

a. Mechanical Construction
The main chamber and the air lock
chamber are made of 3 mm stainless
steel AISI 316L sheet, with the rest of
the auxiliary construction elements of
stainless steel AISI 304 (Figure 4).
The surface finish of stainless steel
is less than Ra<0.6 µm inside and
Ra<1.2 µm outside.
Isolator and air lock chambers
are designed to be hermetic and
leak test compliant with ISO Class 3
classification 14644-7.
Isolator Chambers designs are cGMP
compliant and will be fully welded.
The interior surfaces are constructed

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with rounded corners that provide

smooth interior surfaces and surfaces
that prevent cracking. »» If there is no previous experience in the project
• The doors of the isolator are made
of tempered glass, with inflarable
team, it is important to have the support
gaskets seals. and advice of experienced specialists and
manufacturers of isolators
b. Material Transfer Systems
Inlet:
Air Lock for entry of materials and
utensils of sufficient size. Two gloves
to enable debagging tasks.
FIGURE 6. Outfeed product through split butterfly valve
Drum elevator, prepared for
different sizes, and sealed with
inflatable gaskets during operation
(Figure 5).
Outlet:
Split butterfly Valve Port, to plastic
bag or metal bottle (Figure 6).
Waste Port, a continuous liner, with
inflatable seal port or RTP.

c. Cleaning System
Manual cleaning with spray gun in
the air lock and spray balls and spray
gun in the main chamber. In the airlock
normally only has to be performed
the debagging or unpacking of the
product container. The primary bag
shouldn’t be open in the airlock.

FIGURE 7. Control System Architecture

User Interface LENS – Mix Reality –

M i cro s o f t H o l o Lens Process Instructions for Users & Records.

MES

External Equipment Integration

S ca l e M ett l er To l edo

HMI 1

S i emens Pl at fo r m

PLC

Sensors, instrumentation.
P a s s i o n for life s c i e n c e

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How to set up a Project for Handling High Potent Products under Isolator

»» Projects involving the handling of high potent products are recommended to

be studied and evaluated following some of the reference guides [1,2,3,4,6],
and the current GMP regulations

In the main chamber the product consists of a compact ventilation the highest level of knowledge
will be handled by operator, and module with separate supply and and to carry out a detailed risk
the cleaning of this chamber will exhaust EC fans. The classification assessment. If there is no previous
require a detailed study. Spray balls, obtained inside the chamber is ISO 8 experience in the project team, it is
connected to CIP circuit will allow according to ISO14644. important to have the support and
the cleaning of most of the product In the Air Lock and in the advice of experienced specialists
dispersed along isolator. isolator chamber the ventilation and manufacturers of isolators who
configuration are similar, with the will help to ensure that the result is
d. Control system same functionalities. HEPA H-14 functional and meets the operational
The control system is based on an filtration is foreseen in the supply air requirements.
Industrial PLC connected to sensors and a double HEPA H-14 filter in the
BIBLIOGRAPHY
and detectors level of the isolator for extraction of both the Air Lock and
[1] ICH guideline Q9 on quality risk
its correct operation. This software the main chamber. management.
has an electronic register according The filters are of the PUSH-PUSH [2] ISPE Baseline Guide Volume 1- Active
Pharmaceutical Ingredients.
to GAMP 5 (Figure 7). type so they can be changed from [3] ISPE Good Practice Guide – Assessing
the particulate Containment Performance of
T h i s c o n t ro l s y s t e m c a n b e inside the isolator, allowing a safe Pharmaceutical Equipment (SMEPAC)
integrated with the laboratory’s MES filter change. [4] ISPE Containment Manual- D/A/CH Affiliate
2016.
system.
[5] ISO 14644-7:2004 Cleanrooms and
An interface solution based 6. Mock-up of the proposed associated controlled environments — Part
7: Separative devices (clean air hoods,
on mixed reality technology is solution gloveboxes, isolators and mini-environments)
integrated, in which the operator The manufacture of a mock-up of [6] Spanish INSHT - NTP 1104: Pharmaceutical
industry: classification of active ingredients in
using the isolator will have real- the isolator in disposable material categories. and 1105.
time access to all the information (wood or cardboard) on a scale of [7] Ader A.W., Farris J.P., Ku R.H.,
Occupational health, categorization and
necessary for its correct use. For 1:1 is highly recommended for the compound handling practice systems – roots,
application and future. Chemical Health and
example, he has real-time access to ergonomic study of the isolator. Safety, 12(4), 20-26 (2005).
the standard operating procedures, In this way the user can evaluate [8] Farris J.P., Ader A.W., Ku R.H., History,
implementation and evolution of the
so that he can review each step of the functionality of the isolator pharmaceutical hazard categorization and
the process through the mixed reality for the specific processes defined control system, Chimica oggi - Chemistry
Today, 24(2), 5-10 (2006).
system and avoid errors during the and it can be modified and finally [9] SafeBridge Consultants, Inc., Occupational
Health Toxicity/Potency Categorization and
process. approved after the construction of Handling Practices – SafeBridge, Fifth Revision
In the same way, the operator the definitive model in stainless steel. – January 2002, pp. 12.
[10] Naumann B.D., Sargent E.V., Starkman
himself, through the mixed reality B.S., et al., Performancebased exposure
system, will be able to inform CONCLUSION control limits for pharmaceutical active
ingredients, American Industrial Hygiene
the system of the progress of the Projects involving the handling Association Journal, 57(1), 33-42 (1996).
process, in such a way that there of high potent products are [11] Naumann B.D. Control banding
in the pharmaceutical industry: www.
is total traceability and electronic recommended to be studied and aioh.org.au/downloads/documents/
ControlBandingBNaumann.pdf (last checked
registration of each step. evaluated following some of the on Feb. 3rd 2014).
reference guides [1,2,3,4,6], and [12] Manufacturing Higly Potents Drugs,
reducing the risks, Pharmaceutical Visions,
e. Ventilation and Filtration the current GMP regulations. It is SafeBridge.
System necessary to form a multidisciplinary [13] Markets and Markets, “High Potency APIs
/HPAPI Market worth 26.84 Billion USD by
The ventilation and filtration system team to tackle the project with 2023,” Press Release, 04/18

60 Industria Química Special Achema 2022