Printed by: 168305-3 Date: 15.04.

2014 GMP MANUAL © Maas & Peither AG

11.J Prevention of cross-contamination
Up07 Dr. Christian Gausepohl, Paolomi Mukherji

Here you will find answers to the following questions:

■ What are the causes of incidence of cross-contamination?
■ What fundamental measures should be taken to avoid cross-contaminations?
■ What should be observed when manufacturing critical products such as antibiotics, hormones and zytostatics?

Contamination is generally defined as undesired introduction of impurities of a chemical or microbiological nature, or a foreign matter, into or onto a raw
material, intermediate, or API during production, sampling, packing or repacking, storage or transport (EU-GMP-Guide, Part II, see Chapter C.5).
Cross-contamination is defined as contamination of a starting material or of a product by another material or product (EU-GMP-Guide, Part II, see
chapter Chapter C.5).
Thus, cross-contamination is a special case of contamination.
The risk of accidental cross-contamination arises from the uncontrolled release of materials and products in process, from residues on equipment, and
from operators’ clothing. (cf. 5.18 EU-GMP-Guide). Cross-contamination may occur when different materials or products are handled at the same time
but at different locations, or when different materials or products are handled at the same location one after the other.
One of the central aims of the GMP regulations is to minimise these dangers in order to ensure product quality and patient safety. A range of aspects
must be considered in order to achieve this objective.

11.J.1 Causes of cross-contamination

Possible causes of cross-contamination can be summarized as follows:
■ rooms
■ equipment
■ processes
■ personnel

The prevention of cross-contamination should be adressed by means of a risk analysis during the design phase of rooms, HVAC, facilities and
processes.
11.J.1.1 Rooms
To prevent contamination from dust, it is essential to reduce the development or release of dust to a minimum. To this end, closed systems should
mainly be used. This entails e.g. the encapsulation of machines in which open processes are in progress. Each additional item of pipework etc.
increases the amount of cleaning required – a discrepancy which must be evaluated based on a risk analysis.
Aspiration is an additional important measure for preventing the transfer of dust although it must be ensured that exhaust systems themselves do not
become sources of contamination. Care should generally be taken to prevent fluctuations in the existing negative pressure that would cause a reverse
discharge of dust from exhaust systems. Flexible hose systems that are often used must be kept sufficiently clean or be replaced. Monitoring should
include checks on the effectiveness of measures implemented.
The requirement for sufficient space (3.8 EU-GMP-Guide) can certainly be explained in light of the need to prevent the problems mentioned above.
Rooms that are narrow and/or unclearly laid out are not appropriate for effective cleaning or efficient separation of products or containers.
The conversion of materials in a conversion zone normally involves transfer on in-house aluminium or plastic pallets. These should be cleaned after use or
at regular intervals. The condition of the pallets should be checked during cleaning. Pallets with damaged surfaces (e.g. cracks) must be rejected (see
Figure 11.J-1).
Figure 11.J-1 Unsuitable aluminium pallets with cracks

11.J.1.2 Equipment
Cleaning
The most important aspect for prevention of cross-contamination is cleaning validation (see chapter 8 Cleaning validation), because insufficiently
cleaned equipment directly leads to a carry-over of product residues. Equipment should therefore be cleaned according to product-specific, optimised
cleaning procedures, which have been checked by means of cleaning validation (see Chapter 8.B.2 Compilation of cleaning instructions). A fundamental
prerequisite for reproducibility of cleaning processes is the appropriate design of the equipment according to the principles of hygienic design.
Equipment (such as product containers) that is not cleaned directly on-site should be stored provisionally in such a way that the release of dust is
prevented. This may be achieved by designating a room especially for the storage of contaminated equipment that also acts as an anteroom for a
cleaning unit. Ideally, the material routes of cleaned and contaminated equipment should be kept completely separate. A linear material flow should
therefore be ensured (Figure 11.J-2).
Figure 11.J-2 Linear material flow in the cleaning process

Cleaned equipment and containers must be appropriately stored and protected from the accumulation of dust. For small parts, this may be achieved, for
example, by packaging them in polyethylene (PE) bags. Whenever possible, cupboards should be set up outside the rooms in which production takes
place. The use of open shelving for storage must be avoided as there is a risk of dust accumulation.
It is recommended that visual inspections of equipment, machines, containers and rooms be documented prior to use, e.g. on the cleaning label and in
the batch record. Consistent application normally leads to an increased awareness of these requirements amongst staff.
Utensils
More often than not, it is smaller, more insignificant items that can cause contamination, such as adapter sockets for tubes or pipe connections,
scoops, small measuring containers, etc. (see Chapter 11.C.2 Cleaning and Chapter 11.H Identification).
11.J.1.3 Processes
Process-related risks
All individual process steps should be subject to a risk analysis with view to their potential risk of cross-contamination. Processes with open handling of
raw materials, intermediate products or finished products are most critical in this context. Examples for this are weigh-in, sampling, filling and packaging.
This risk can be reduced by use of closed equipment wherever possible.
The check for complete depletion of equipment at the end of each process step as well as the check for cleanliness prior to each processing step are
fundamental requirements for the prevention of cross-contamination. These controls should be part of each manufacturing and packaging instruction.
Packaging processes
In packaging areas, different products are simultaneously packaged in different ways near one another. This makes high demands on rooms, facilities
and the process organisation. The line clearance fulfils an essential prerequisite for the prevention of contamination and mix-ups (see Chapter 13.B.3
Line clearance).
Labelling
The labelling of equipment and containers is extremely important, particularly with respect to the consistent declaration of the cleaning status (see
Chapter 11.H Identification). They must always be labelled before being used in the production process. Start-ups from equipment that are not classified
as acceptable products for safety reasons must be declared to prevent incorrect assignment to acceptable goods.
Waste diposal
Waste must be disposed of as quickly as possible. Production waste must be collected outside the production area. This must be ensured as part of the
organisational process.
11.J.1.4 Personnel
Clothing
The suitability of working clothing is also important for the prevention of cross-contamination. The re-release of particles and dust must be regarded as
critical. Outside pockets are a potential source of danger in every cleanliness grade (see Chapter 11.B.1 Clothing). The transfer of dust due to personnel
movement should be minimised by cleaning rooms and corridors regularly. Dust trap mats at the transition areas between rooms and in locks help
minimise the spread of dust from such rooms and must be cleaned regularly.
The intervals for change of clothing have to be defined with regard to the following aspects:
■ kind of equipment (open/closed)
■ kind of product (dusty/liquid)
■ kind and duration of processes
■ batch size and API content in the formulation
■ clothing material (adsorptive/emittant)

Gloves should always be changed when entering a production room. The effectivity of the clothing concept has to be monitored.
Code of conduct
Training should be carried out on a regular basis to make personnel aware of the consequences of cross-contamination, misidentification and mix-ups.
Regular analysis via discussions on this subject helps pinpoint company-internal weaknesses and allows suitable remedial measures to be taken. (See
Chapter 2.C Training.)
Furtheron, the behaviour in critical situations should be addressed in training sessions. One example for this is shown in Figure 11.J-3.
Figure 11.J-3 Behaviour in critical situations
Emergency spill cleanup procedure

■ Quarantine of area
■ Cleanup of area
■ Quarantine of all product(s) possibly affected
■ Testing of all product(s) possibly affected
■ Follow deviation procedure and documentation requirements for incidents

11.J.2 Measures to prevent cross-contamination

“Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.” (5.20 EU-GMP-Guide,
see Chapter C.4.5).
Checks of this kind may be carried out as part of the self-inspection (see Chapter 18.E Self-inspection). The check points are then established so that
an evaluation may be carried out for the period concerned.
Measures to prevent cross-contamination may be technical or organisational. Generally, potential causes of cross-contamination have to be identified
and the risk of carry-over has to be reduced. Both from a GMP view and from a safety view, closed facilities are favourable. Individual parts and the
associated assembling and disassembling steps should be minimized. If necessary, tools, equipment, rooms or even entire facilities have to be
dedicated to specific products.
Figure 11.J-4 gives an overview on measures to control the risk of cross-contamination.
Figure 11.J-4 Measures to control the risk of cross-contamination
Measures to control the risk of cross-contamination

■ Evaluation of process steps and material flow

■ Minimization of the number of process steps (process optimization)
■ Minimization of product-contact individual parts
■ closed systems
■ CIP cleaning
■ pressure differential cascades and locks
■ appropriate change intervals for clothing
■ robustness of quality systems (documentation, training, …)
■ dedicated tools, equipment, rooms or facilities
■ periodic review of effectiveness (e.g. by self-inspection)

Containment Facility Designs and Procedures

Containment facility designs and procedures should be established to cover containment requirements for airborne product/active component handled in
a dedicated facility. Monitoring outside of facility is required to verify that containment is working.
The facility design for a non-dedicated facility should take into consideration air flow patterns, maintenance of pressure differentials, dust
removal/filtration, HVAC preventative maintenance and cleaning, material flow patterns, personnel flow patterns and personnel gowning requirements.
The containment procedures for a non-dedicated facility should cover storage and handling of special danger products and APIs, handling of open
containers of APIs, handling of APIs during compounding and handling of spills of product, bulk product and API.
The containment attributes of dedicated and non-dedicated facilities should be validated and documented.

11.J.3 Manufacture of critical products

Specific products should be processed in “dedicated and self contained facilities” (3.6 EU-GMP-Guide). These include “highly sensitising materials (e.g.
penicillins) or biological preparations (e.g. from live micro-organisms)”.
The contamination risk associated with such products implies the need for a dedicated, separate manufacturing site. If this manufacturing site is located
at a company's premises where conventional production is also carried out with similar logistics, it must be ensured that equipment cannot be mixed up.
Separate ventilation systems should exist. At the concept stage, care should be taken to ensure that the air discharge and air intake of separate units
are not located near one another (see Chapter 3.G Heating Ventilation Air Conditioning (HVAC)).
The risk to other products must be regarded as very high. To prevent the dissemination of dust, only copies of the batch records should leave the area
(e.g. via fax), because they are kept near the product. The use of an electronic documentation system is advantageous. (See Chapter 15.C Batch
documentation). If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-
penicillin drug product should be tested for the presence of penicillin. Such drug product should not be marketed if detectable levels are found when
tested according to specified procedures (According to 21 CFR 211.176, Penicillin Contamination, see Chapter D.1.2).
“[…] certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products
should not be conducted in the same facilities.” (3.6 EU-GMP-Guide).
In such instances however it is possible to employ conventional production options during the course of manufacturing campaigns. Special precautions
should be taken. These include the special labelling of manufacturing equipment or rooms in addition to facility-related precautions.
The risk posed by critical processes can be reduced by segregating them either physically or temporally. A cabin enclosure is an effective means of
achieving physical segregation. In this case, the effectiveness of the cabin enclosure measures must be checked during qualification. The area of air-
conditioning technology (air exchange rate, pressure differential, proportion of fresh air to recirculating air (see Chapter 3.G Heating Ventilation Air
Conditioning (HVAC)) is especially relevant. In so-called clean corridors, the corridor in front of the production cabin has a positive pressure in relation
to the cabin which minimises the spread of dust from the cabin. The quality of the corridor (no contaminated equipment or other potential dust sources
present) and efficient performance of the door-closing mechanism (short opening times) are basic requirements (see Chapter 3.D.2 Doors and windows).
The risk of dust being carried out via clothing can be countered by wearing special outer clothing and by cleaning shoes. The use of dedicated equipment
should be anticipated in many cases particularly if the pharmaceutical ingredient is highly potent and the cleaning is classified as critical (e.g. textile
filter bags from fluid bed equipment, tubes that come into contact with products).
Special protective clothing for personnel (in the interests of health and safety at work) should be left in these areas, i.e. a protective suit worn over
normal clothes must be removed in the designated area and not outside of it. The contaminated suits are wrapped up, e.g. in bags, and then removed.
Training has a significant role to play in this regard. Emphasis should be placed on the cleaning of normal clothes prior to leaving the area (e.g. shoe
soles: sole cleaning devices and dust trap mats may prove to be useful). It must be clear to staff that simple oversights (such as the removal of breathing
masks prior to cleaning) may endanger other products being manufactured. Steps must be taken to ensure that protective equipment does not become
contaminated, for example when large quantities of dust are produced. This can be achieved by compartments and cupboards.
“[…] The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises […]” (3.6 EU-GMP-Guide, see
Chapter C.4.3).
As a consequence, pesticides, herbicides etc. must not be manufactured in premises that are used to manufacture medicinal products. General checks
should be carried out to verify whether the manufacture of a given product influences the manufacturing process and overall quality of another product
manufactured nearby. This proximity could be of a physical as well as temporal nature. These rules also apply for the equipment used as well as for the
rooms: “Normally, the production of non-medicinal products should be avoided in areas and with the equipment destined for the production of medicinal
products.” (5.17 EU-GMP-Guide). The manufacturing of food or cosmetics is undoubtedly less critical. In terms of organisation however, this should be
separated from pharmaceutical production.
Summary
Cross-contamination can be prevented by a number of different measures that must be coordinated with one another. One of the main rules to be
observed is the temporal and/or physical segregation of different products during their manufacture and the cleaning of rooms and facilities.
Critical products such as antibiotics, hormones and zytostatics must be manufactured in separate rooms.