Defects in the pharmaceutical sector - GMP

Good Manufacturing Practices (GMP) in the pharmaceutical sector provide a set of guidelines, instructions and requirements on the basis of which the production and packaging processes of medicines must be organised and managed, in order to ensure that product quality and end-patient safety are always guaranteed.

During the manufacture and packaging of a pharmaceutical product, there are many aspects to keep under control and the processes must be “designed” in such a way as to ensure compliance with the relevant standards and expected quality characteristics. Given the multitude of factors at play, having a robust and repeatable process allows for a degree of confidence that makes the production process reliable and sustainable.

In this article, we will provide an overview of the main categories of defects that can be generated during the manufacturing and packaging processes of pharmaceutical products.

A defect is defined as a product that does not comply with expected quality and safety standards and represents a potential risk to patient health.

Defects can be of various types and have different impacts, so they are classified according to their characteristics and criticality.

AIFA has provided guidelines for correctly reporting various defects.

We can distinguish between four main types of defects:

• Labelling defects
• Packaging defects
• Chemical/physical defects
• Defects related to contamination and sterility

Labelling defects refer not only to the total or partial absence of data or information required on the primary packaging (bottle, blister pack, strip, etc.) or secondary packaging (box and leaflet), but also to its incomplete legibility or inaccuracy.

This type of defect includes information such as variable data (batch number and expiry date), dosage information, barcode, AIC number, information on the label and in the package leaflet (e.g. method of administration, dosage, side effects, etc.).

A packaging defect is defined as a non-conformity relating to the closure, filling/contents or functioning (e.g. malfunctioning spray device, poor dispensing of dropper, lack of adhesiveness of a transdermal patch, etc.), damaged or missing product (e.g. broken tablets, open capsules, broken vials, melted or malformed suppositories, etc.) and safety seals/closures (malfunctioning or ineffective child-proof and tamper-evident closures). This type of defect may also include product mix-ups.

A chemical/physical defect refers to a non-conformity of the actual pharmaceutical product (injectable solution, syrup, tablet, etc.) or its incorrect “availability” (e.g. incorrect quantity inside the package or non-compliant quantity of active ingredient).

This type of defect includes non-conformities relating to the organoleptic characteristics of the product (colour, smell, taste), solubility (solubilisation and/or reconstitution of the product) and coating (modified release, gastro-resistance, coating, etc.).

These defects can be caused by both the manufacturing and packaging stages and are sometimes linked to packaging defects, such as an incorrectly sealed blister pack, which can allow moisture to enter the primary packaging, resulting in the degradation of the tablet inside.

Contamination of a pharmaceutical product can be of various kinds, mainly distinguishable as follows:

• Chemical contamination (presence of substances not included in the product formulation)
• Microbiological contamination (presence of microorganisms)
• Physical contamination (presence of foreign bodies)
• Lack of sterility

The types of contamination listed above can have various origins. They can be caused by the production process (equipment, procedures, operating personnel) but also by the raw materials used or the packaging materials.

Quality defects are classified according to their severity and danger. The same type of defect can be classified differently depending on where it is found. For example, the lack of variable data is more serious when it occurs on the primary packaging than when it affects the secondary packaging.

In general, defects are classified as class 1, 2 and 3, and this classification is also used for reports of defects by patients, pharmacists, doctors, etc. (market complaints).

This class includes the most critical defects that pose a potential risk to life or a serious risk to patient health.

Examples of this class are:

• Incorrect active ingredient (label does not match contents)
• Incorrect dosage
• Microbial contamination of injectable, ophthalmic or sterile products
• Non-visible chemical contamination (incorrect substances within the product or degradation products thereof)
• Lack of variable data on primary packaging

This class includes defects that could lead to incorrect treatment of the disease or cause discomfort to the patient.

Examples of this class are:

• Incorrect labelling (e.g. text and/or images with errors or missing)
• Missing or incorrect information in the package leaflet
• Microbial contamination of a non-injectable, non-ophthalmic and non-sterile product
• Visible chemical or physical contamination (significant impurities, particles, cross-contamination)
• Non-compliance with product specifications (e.g. stability, volume/weight, available dose, etc.)
• Incorrect/unsafe closure of specific types (child-proof closure) or hazardous products (e.g. cytotoxic drugs)

This class includes defects that do not pose a significant risk to patient health but which nevertheless result in the product not complying with the expected quality characteristics.

Some examples of this class are:

• Missing or incorrect variable data on secondary packaging
• Missing product in non-life-saving medication
• Defective closure resulting in product loss.
• Devices not functioning correctly in non-life-saving products (e.g. nasal sprays, nebulisers, etc.)
• Broken or damaged product
• Product not fully compliant with expected characteristics, resulting in difficulties in use (e.g. incision mark not perfectly marked on tablets, lack of dropper, etc.).

Finally, there are so-called ‘cosmetic defects’ that do not affect the quality, reliability, or effectiveness of the product but do affect its appearance (dented packaging, bent but still legible label, crooked label, etc.).

Every pharmaceutical manufacturer is required to identify and manage defects found in its products both during the production phases (internal deviations) and in subsequent distribution and sale (market complaints).

GMPs provide guidance on the management of deviations and complaints, but the most important recommendation is to use robust, reliable and repeatable processes that minimise defects and quickly detect any defects that do occur.

This can be achieved by qualifying and validating the equipment and processes in use.

During the validation phases, all critical parameters that could potentially generate a defect are challenged and the control systems that allow the defect to be detected and removed if it occurs are verified.

Good qualification and validation can certainly lead to a drastic reduction in defects during production. 

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