25.09.2015 |

LOGFILE No. 03/2016 – Possible risks of manufacturing and packaging

Possible risks of manufacturing and packaging

An excerpt from GMP Fundamentals 

by Dr. Christine Oechslein

Contamination

Contaminants are impurities from all quarters that can affect the product or intermediate. Contamination can reduce the quality of the medicinal product and lead to premature spoilage. Cross-contamination refers to the contamination of a product by other active ingredients or other products. Both types of contamination must be avoided at all cost.

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Contaminants always find their way into a product, and because there are so many different sources of contamination, a large number of protective measures have to be taken – and they have to be taken simultaneously.

Persons as a source of contamination

Clean room clothing can only prevent hair and skin from being shed in the room if it is put on and worn correctly and changed regularly. When a product changeover is carried out, the clothing has to be changed as well. At least the gloves and sleeves should be changed to ensure that the dust on the clothing does not contaminate the next product that is processed. Personal hygiene, thorough washing of hands and regular change of gloves help prevent bacteria or microorganisms entering the product.

Materials as a source of contamination

Even if the starting materials themselves meet all requirements, the containers are often dirty. For this reason, materials may only be brought into the weighing and manufacturing areas using the material lock. The dusty outer cardboard or foil is removed there, the pallets are exchanged or the outside of the container is cleaned. Containers with raw materials or (intermediate) product should remain closed to ensure that dust cannot escape and nothing can fall into the container. This also applies to empty clean containers. If packages are opened too quickly and without prior thought (tearing, unsuitable knife), the dust can escape or pieces of the packaging material can fall in.

Equipment as a source of contamination

It is vital that later products are not contaminated with residues from an earlier product that were not removed from containers and facilities, or with residual cleaning agent or rinsing water. For this reason, the cleaning instructions that apply specifically to a particular device or facility must be strictly observed. The concentration of the cleaning agent, the application time, the duration or amount of final rinsing, the drying period and subsequent dry storage are especially important.

A check to ensure the equipment is visually clean after cleaning and prior to its next use is a simple and extremely effective way of detecting dirt and avoiding contamination. If hoses, seals and filters are difficult to clean, they should only be used for a specific product (dedicated equipment). Scoops and sampling utensils must be kept clean. They may only be used for other products after thorough cleaning to prevent the transfer of product residue.

Room air as a source of contamination

The design, qualification, maintenance and monitoring of ventilation systems for manufacturing rooms is very costly. Nevertheless, whether this large investment pays off depends on the correct behaviour of personnel.

Even the smallest of errors can cancel out the best ventilation system. Open doors undo the sophisticated pressure differences and air exchange and allow dirt and API dust to enter unhindered. Rooms that are packed full with materials and machinery or blocked air inlets prevent the air from moving as it should. Dust can gather and spread. Two different products must never be opened and processed at the same time in the same room because of the risk of cross-contamination.

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Mix-ups

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Different substances or mixtures with different mixing ratios, e.g. active ingredients, powder mixtures, finished tablets or solutions, often look similar at first sight. A mix-up between two products or two different doses of the same active ingredient during manufacture can have life-threatening consequences for the patient if the error is not discovered during the final analysis of the product. It is even more difficult to find one tablet or capsule in a product that does not belong there or individual packages that are incorrectly labelled. For this reason, the utmost care must be taken to prevent mix-ups.

Four key measures can be taken to avoid mix-ups:

Functional design of the material flow and personnel flow

If several products are manufactured simultaneously in one room, mix-ups or cross-contamination can occur. For this reason, the "one product per room"rule applies.

If the paths of products from different manufacturing phases cross, i.e. if these products are placed next to each other for a short time in staging areas, mix-ups can easily occur. There is an increased risk of contamination and mix-up if several different products are processed by personnel at the same time. For this reason, the room layout and work processes should be planned so that the different products or products from different manufacturing phases use different paths.

Identification of materials, containers, rooms and machines

Rooms must be labelled to indicate their operational status. It must be possible to see from outside which product is being manufactured in the room, if cleaning or servicing is in process, or if the room is clean and ready for use for the next production setup.

The same applies to raw materials, intermediate products, samples, containers, pipeline points of use (taps), facilities and machines. Labels or signs must be attached to them to identify the material or product they hold at all times. If appropriate, the label or sign should indicate the stage of production, ID number, batch number, product status (released, quarantined, rejected) and cleaning status (cleaned/not cleaned).

Identification and label control

The names of active ingredients are often complicated and ID numbers are long, but it is vital to check every label on every single container before use. If it is not possible to use a scanner for identification, the staff member is obliged to read the labels carefully and compare them with the information contained in the bill of materials or manufacturing and packaging instructions.

Line clearance (controlling the complete removal of the previous product)

During each product changeover, all of the previously used product, input materials, packaging materials, labels, analysis and stability samples, documents, materials and waste must be carefully removed from the facility and workplace. Checklists help to ensure that nothing is forgotten and that all areas of the facility that are difficult to access are checked. A single forgotten label or a single tablet that is not removed can have fatal consequences. For this reason, the line clearance must be checked on site by a second person (four-eyes principle) and documented in the manufacturing or packaging record.

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