According to ISO 9001:2015, quality is: “the degree to which a set of inherent characteristics of an object fulfill requirements”.
Quality Assurance
The planned and systematic activities implemented in a quality system so that required quality standard for a product or service can be fulfilled.
QA is therefore proactive in its nature and it is targeted in designing and managing all production processes in such a way to reduce as much as possible the occurrence of defects and problems in manufactured products.
Quality Control
The procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer.
QC is therefore reactive in its nature, it is targeted to find and remove from production stream all products which are not compliant with quality requirements.
It is extremely important to highlight that while this document is entirely focused on inspection Quality Control (QC) process, the removal of defective products can never be 100% accurate and therefore a careful management of the whole production and Quality Assurance (QA) process are likewise essential to reduce as much as possible any cause of defective or contaminated products in the first place.
Neither QA or QC process alone can guarantee 100% good results. They should always work together to help each other to achieve the most effective and stable results on final product quality.
Quality Control in parenterals
Main inspection/quality items to be checked
After the introduction of QC and QA concepts we’ll start now diving more in detail about quality control in parenteral products and which main quality aspects are regulated by main pharmacopeias and are commonly checked worldwide in production facilities.
There are obviously important differences and changes in time and among different countries, however we can list the following most important categories of visual controls in parenteral products.
Visible particles
Cake appearance and features
Container Closure Integrity
Other visible defects (cosmetic)
Additional container defects
We already discussed in part 2 how the most critical aspect to be controlled before releasing the products to the market and to the final users is the safety of the product, then it comes its proper function and finally come minor defects as cosmetic or appearance.
The safety of products can be harmed by two main problems:
the presence of foreign particles into the container, specially extrinsic (see part 2), which by definition implies the lack of sterility
the lack of integrity of the container so that microorganisms from outside can enter and contaminate the product
According to these principles, the most important visual controls performed on 100% of production are for particles and closure of the container.
The other controls (cake, cosmetic, etc) are usually performed at the same time but are less critical and receive less attention and resources.
Regulations, definitions & guidelines about visible particles
Starting in 1942 when the USP and the American Pharmaceutical Association (publisher of the National Formulary at that time) stated that aqueous injections should be “substantially free” of particles discernible with the naked eye, the definition eventually evolved into those currently used by the three major Pharmacopeias stating that injectable drug products should be “essentially free” (USP), “practically free” (European Pharmacopeia) or free of “readily detectable” (Japanese Pharmacopeia) visible particles.
Most recent requirements require each and every unit of injectable product to be inspected as part of the routine manufacturing process (100% inspection).
It is recommended to execute inspection where defects can most easily be spotted, typically after sealing and before labeling.
Each unit can be examined manually by unaided eye (Manual Visual Inspection or MVI) or by using a conveyor system to transport and present the containers to a human inspector (Semi-automatic inspection) or by means of Automatic Visual Inspection (AVI) machine.
Manual and semi-automatic inspection should only be performed by trained, qualified inspectors.
The intent of this inspection is the detection and removal of any observed defect.
When in doubt, units should be removed.
Requirements from main Pharmacopeias
EP requires “Practically free” of visible particles
USP requires “Essentially free” of visible particles
JP requires “free from readily detectable foreign insoluble matters”
For a very long time this kind of unclear – non objective requirements have put drug manufacturers in a difficult position. However recently, the FDA and the other regulatory agencies have moved forward to make requirements and procedures more standardized, clear and easy to implement, fulfill and assess.
After several enhancements and harmonization processes to make all pharmacopeias more similar, the regulation is currently based on three main steps :
The manufacturing processes and associated controls are designed to yield a product free from visible particles to the extent possible.
Visual Inspection (100%) is performed at the end of drug product manufacturing
Visual Inspection is followed by sampling inspection (AQL sampling) to confirm the “Essentially free” requisite before releasing the batch to the market.
Regulations, definitions & guidelines about Container Closure Integrity (CCI)
Similarly to requirements for visible particles, the three main pharmacopeias contain general requirements about integrity of closure and are subject to a process of evolution through time and common harmonization.
USP “The packaging system should be closed or sealed in such a manner as to prevent contamination or loss of contents”
21 CFR “Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product”
JP “Hermetic containers or tight containers which are able to prevent microbial contamination are usually used for the preparations”
EP “The tightness of the container is ensured by suitable means. Closures ensure a good seal, prevent the access of micro-organisms and other contaminants and usually permit the withdrawal of a part or the whole of the contents without removal of the closure”
As we will see more in detail in the next part, the CCI testing can be nowadays performed by visual inspection and by other non-visual technologies (high voltage, pressure decay, laser adsorption, etc).
Consequently current regulations focus more on the result and the validation of the whole process regardless of the specific inspection system/technology used.
It is therefore required to first evaluate and assess the risk of lack of integrity and take every possible measure to prevent its happening (QA approach). Then it is required to take the best possible approach to detect and reject from production all containers whose integrity is not guaranteed (QC approach).
About Author: Mr. Stefano Arletti, since 2013, he has joined Tofflon introducing and developing Automatic Inspection Machines Development. He is responsible for automatic vision inspection machines to worldwide Pharmaceutical Industry. He has developed several new ideas patented under Italian and European Patent Offices.
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