ABSTRACT

Pass Boxes and Its Importance

in Minimizing the Risk of
Cross Contamination in
Pharmaceutical industry.

Varadharaj Vijayakumar
B. Pharm MBA (Pharmaceutical
Management)

Core Areas: Aseptic

Practices/Qualification and Validations,
Sterility assurance, Isolator Techniques
with VHP cycle developments. Risk
assessment/QMS, Sterile manufacturing
Gap assessments/ Lyophilisation.
Pass Box and Its Importance in Minimizing
Email: vino04_pharma@yahoo.co.in
the Risk of Cross Contamination in
LinkedIn:
Pharmaceutical industry
http://linkedin.com/in/varadharaj-
vijayakumar-13004819
Pass Box and Its Importance in Minimizing the Risk of Cross
Contamination in Pharmaceutical industry.

Hi Readers!
This Paper describes about Pass Box and Its Importance in Minimizing the Risk of Cross
Contamination in Pharmaceutical industry.
Introduction:
In a Pharmaceutical Manufacturing facility where a sterile environment is utmost, but an equal
importance must be given to ensure the movement of materials that does not compromise the purpose
of the cleanroom.
Operators account for the highest source of contamination, around 80% of all contaminants found in
cleanrooms can be drawn back to operators.
In all Pharmaceutical Clean Rooms, One of the systems commonly used to minimise contamination is
the pass box.
So what is the only work given to Pass Box?
As a Name itself suggests the work of Pass box.
Pass Box=Pass –Permitting; Box- Rigid Case. Pass Box which is also called as transfer hatch Box,
Pass-through Box or SAS pass (sterile access system), which works as a barrier between areas with
different levels of cleanliness in the cleanrooms.
Hence Pass box is used to transfer the material between two areas generally between the clean room
area with same classified area or the controlled area and an unclassified areas so as to avoid airborne
cross-contamination.

Types of Pass Boxes In Pharmaceutical Industry:

There are three types of pass box used in the pharmaceutical industry
1. Static Pass Box
2. Dynamic Pass Box
3. Biological Pass Box
Note: It can also be defined by the End User for their right configuration

Definitions:
Static Pass Box:
Static or passive pass box which is designed for the transfer of materials between areas with the same
cleanliness class, without a filtration system.

Dynamic Pass Box:

Dynamic Pass box is also called as Ventilated Pass Box which is designed for passing/transfer of
materials between classified areas or between a classified area and a non-classified area, with blowers
and HEPA filters which sweeps the air.

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Pass Box and Its Importance in Minimizing the Risk of Cross
Contamination in Pharmaceutical industry.

Biological Pass Box:

This type of pass Box is used for the transfer of materials for biological neutralisation of elements and
bio-contaminated materials between classified areas, or a classified and a non-classified area. This
type is equipped with a bio-decontamination system through filtered air and sanitization happens by
using hydrogen peroxide generator which can be fixed internal or externally.

How Pass Boxes helps in the preventions of Cross Contamination in

Pharmaceutical Clean rooms?

In cleanroom there are different transfers such as movement of Dispensed API, Excipients material,
Gloves, Used Garments, Product Filtration tanks, Scraps, Dirty Materials happens between classified
areas or between a classified area and a non-classified area.
During these transfers criticality should be assessed while handling dispensed materials, sterile
articles, and filtered product vessels.
Hence materials between a classified area and a non-classified area should be taken utmost care to
avoid cross contamination on the materials which gets transferred from non-classified area to
classified area.
This cross contamination is prevented by sanitization of Pass box and materials for defined period and
the environment of pass box gets air sweeping through HEPA filters. This ventilation system coupled
with air filtration which ensures a clean environment inside the chamber before the opening of the
door.
However Static pass boxes must never be used to transfer material between clean and non-clean
rooms.

Design of Pass Box:

Standard material of construction is stainless steel so that there is no adverse reaction while using
different disinfectants such as hydrogen Peroxide and other cleaning agents.
Pass Boxes should be integrated with the cleanroom wall Panels. It should be durable, aesthetically
pleasing and sit flush to the cleanroom walls, so that the accumulation of dust is completely avoided.

Dynamic Pass Box:

These are equipped with suction filter made of stainless steel and filters such as Fresh air –Efficiency
90% down to 10 μ, Pre filter- EU 6 - Efficiency 95% down to 5 μ and HEPA filter -EU 14 -
Efficiency 99.99% down to 0.3 μ
Iinterlock system which controls the inlet and the outlet of the pass box so that doors are not opened at
the same time. This will help in avoiding cross contamination.

Static Pass Box:

Since these are simple boxes (installed between the same classes) and are made with stainless steel
(304/316). There is interlock system which controls the pass box so that doors are not opened at the
same time. Static pass box also contains UV Light along with hour meter. This will help in avoiding
cross contamination.

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Pass Box and Its Importance in Minimizing the Risk of Cross
Contamination in Pharmaceutical industry.

What are the basic requirements considered in User Requirement

Specification for Dynamic Pass Box?

1. Blower shall be mounted on top of the pass box. Blower ON/OFF switches to be provided on
the pass box with Indications
2. Supply HEPA filter shall be H 14 grade (99.999 @ 0.3 Microns).
3. Should contain Pre filters of 10 or 5 Microns size.
4. High Compact Fluorescent light with acrylic diffuser.
5. Touch Switch for UV Light (If considered by user) & Microprocessor base blower On/Off.
6. Magnehelic gauge (0-50 mmWc) to read the pressure across the PRE filter and HEPA filter.
7. Hour meter (Digital) for monitoring usage of UV light with resettable option.
8. Upstream & DOP Port for checking the upstream challenge of the HEPA Filter.
9. Electromagnetic Door interlocking and Indicators shall be available on both sides of the door
interlocking.
10. Doors with SS 304 handles, SS 304 hinges and double glazed view panel.
11. Air Velocity at 6 inch below the HEPA filter shall be 90 FPM ± 20%.Air flow shall be
vertical and re-circulatory.
12. Low Noise and Vibration.
13. Cleanliness class Equal to or better than ISO Class 5 at “AT REST” condition.
14. Light level shall be NLT 300 LUX.
15. Material of construction, typically SS 304.
16. Inside corners should have a smooth bed (Coving) for easy cleaning.
17. Gaskets should be food grade.
18. Toughened glass in the doors of pass box.
19. Access should be sufficient for maintenance work for the blowers and HEPA filter
replacements.
20. Uninterrupted power should be provided.

Major Expectations for Users:

Below are some major expectations for Pass Boxes…

 Transfer process should be validated by air visualization studies under empty and loaded
worst case.
 Air visualisation studies in “at rest” and “in operation” condition – verify no Grade C air can
enter Grade B.
 Recovery Studies to be performed at Rest and loaded conditions.
 Interlocks, Alarm system and hold time to be validated.
 SOP for transfers should be available and SOP should have a full list of items that are passed
through pass boxes.
 Preventive maintenance checklist should be in place along with instrument calibration details.
 Environmental Monitoring of pass boxes and operators should be trained for operating pass
box and its transfer procedures.

Preventive Maintenance of Pass Box:

Below are few critical points which should be ensured during preventive maintenance of pass box.
1. Running condition of the Pass box.
2. Any Abnormal sound

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Pass Box and Its Importance in Minimizing the Risk of Cross
Contamination in Pharmaceutical industry.

3. Base bolts of blower and motor(Tightened)

4. Physical condition of the filters.
5. Loose connection of wiring
6. Greasing motor and blower bearings.
7. Control panel with air blower, locating hanging wires.
8. Panel Earthing checks
9. Checking control panel relays.
10. Voltage checks
11. Gasket checks
12. Checks for UV lamp, door limit switch and safety interlocks.
13. Motor Loads.
Note: The above mentioned points are completely based on author experience, which can also be
increased based on frequency of PM Activity.

Regulatory Observations:

1. The pass-through box installed between the Buffer Room and Anteroom is composed of a
white, laminate wood material that is peeling away from the box frame.
2. No smooth finishes observed and
3. Dust particles accumulated.
4. Inadequate Smoke studies for pass Boxes were observed.

Requirement of UV installation in Pass Box?

Installation of UV Light in the dynamic pass box is optional. However if UV Light is installed in the
pass Box then the validation of UV and its efficiency should be performed.
For validating UV efficiency of a pass box it’s tested using the microbiological challenge test.
This is carried out simulating exactly the real operative condition. For this test Bacillus subtilis is
usually used as a challenge microorganism.

How to perform?
Basically, this test consists of the exposure of Petri dishes with culture medium, which is inoculated
with a certain concentration of Bacillus subtilis. These plates are then exposed to UV radiation for the
specified time so that the efficiency of UV inactivation can be studied.

Typical Validation Requirements for pass Box:

There is not a standard that defines the methodology to qualify a pass box, but it is possible to accept
the principles given in ISO 14644 and other standards because these boxes work much the same as a
unidirectional airflow device.

Qualification frequency in a year Reference/Acceptance Criteria

Qualification Grade A &

Sr. No Test B Grade C & D

The average airflow velocity should be

1 Air velocity Twice Once 0.45 m/s +/- 20%.

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Pass Box and Its Importance in Minimizing the Risk of Cross
Contamination in Pharmaceutical industry.

Non-viable Refer standard ISO 14644-3.

2 particle count Twice Once

As per the limits based on cleanliness

classification-in house.
Microbial Note: Higher grade class shall be
3 monitoring Once Once considered in defining the limits

Leaks should not have a penetration

4 Filter integrity Twice Once greater than 0.01%.

The smoke should flow smoothly, drawn

from the release point towards the slots in
the bottom or the sides of the pass box.
Airflow Also accepted Based on classification it
5 visualization* Initially Initially (internal criteria can be defined)

Not more than 15 min-Refer standard ISO

6 Recovery study Initially Initially 14644-3.

Note: Grade-A yearly once. *Airflow visualization should be repeated once any major changed done in the
system. (E.g. filter change), however for Grade B class it can be reduced to twice in a year based on risk based
assessments.

Conclusion:

Contaminated environments can lead to product recalls, regulatory observations, fines, or even
consumer deaths. In order to prevent, and monitor microbial contamination in cleanrooms, several
aspects of cleanroom must be understood.

Cleanroom encompasses a wide variety of subjects, including, cleanroom design, material transfer,
personnel and material flow, cleanroom gowning, personnel behaviour, aseptic technique,
environmental monitoring, data trending, cleaning, sanitization, and disinfection.

From the brief Understanding with respect to types of pass boxes, design aspects, validation
methodologies, risk assessment , user requirement concepts , sanitization on transferring material’s in
clean room using pass boxes plays prominent role important to avoid cross contamination and control
the cleanroom environment and risk to patient is Nil.

References:
 The FDA recommends in their guidance for industry - sterile drug products - produced by
aseptic Processing — current good manufacturing practice (September 2004 pharmaceutical
cGMPS).
 European Commission EudraLex "The Rules Governing Medicinal Products in the European
Union" Volume 4, EU Guidelines for Good Manufacturing Practice, Medicinal Products for
Human and Veterinary Use, Annex 1 - Manufacture of Sterile Medicinal Products.
 United States Pharmacopeia (USP) <1116> Microbiological Control and Monitoring of
Aseptic Processing Environments

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