GMP requirements for pharmaceutical Equipment can be divided into five key categories:
· Equipment must not adversely affect product quality.
· Equipment must be easy to clean.
· Equipment must comply with applicable technical regulations.
· Equipment must be suitable for its intended use.
. Equipment must comply with application document requirements
1. Equipment must not adversely affect product quality
There must be no interaction between the surface of equipment parts that are in direct contact with the drug and the drug that hurts the quality of the drug. For example, for a blister packaging machine, the feeding part of the equipment will come into direct contact with the medicine.
The Equipment must not release substances or adsorb drug components, and they must not chemically react with each other. The Equipment must not release substances that are harmful to the quality of the drug (lubricants, rust, or wear of the Equipment pose such a risk). If wear is unavoidable, the adverse effects on the quality of the drug must be within a tolerable range, which requires the control of the material type of the Equipment and the type of substances released.
2. Equipment must be easy to clean
The requirement of “equipment must be easy to clean” can be found in the GMP documents of almost all national regulatory agencies, including two goals:
a. The surface (generally refers to the surface of the parts in the Equipment that come into contact with the drug) should be smooth.
Smooth-surfaced devices are easier and more effective to wipe or rinse, while devices with scratches or cracks on the surface are pure hygiene risks. These scratches may provide a hiding place for bacteria, making it difficult to clean, disinfect, and eliminate bacteria; drug residues may be trapped in these scratches and gradually integrated into subsequent production batches, causing cross-contamination. The potential survival or retention of microorganisms in cracks or scratches can have a significant impact, especially in producing sterile drugs. This is because microorganisms can multiply, and a small number of bacteria may multiply in large numbers quickly, which means that microorganisms will contaminate drugs during the production process. Even if no active bacteria enter the drug, their metabolites or cellular components may cause significant problems. These substances are called endotoxins and may cause fever if administered parenterally. 0.8 microns is a generally accepted surface roughness. In addition to cracks and scratches, the seals of the Equipment, that is, the small gaps between the seal/gasket and the sealed part, may also have the abovementioned problems.
b. Hard-to-reach areas in the Equipment, also known as “recess corners,” these recess corners are areas in the Equipment that are difficult to clean.
For example, the blister packaging machines, the feeding area of the equipment is extremely important, and recess areas should be avoided as much as possible.
The 1972 draft of the FDA’s “Large Volume Parenterals Guide” (LVP), 2I CFR Part 212.49, first mentioned the rule to prevent dead spots. This requirement was adopted in the 1993 FDA’s “Guide to Inspection of High Purity Water Systems”. The recess corners rule reappeared in the 2001 ISPE Guide. The ISPE Baseline Guide “Water and Steam” talks about the 3D rule. It was further mentioned in WHO TRS 929 (1.5D), WHOTRS 970 (3D), and ASME BPE.
In general, whether you are producing sterile or non-sterile drugs, you need to avoid areas in the Equipment that are difficult to clean. These areas are breeding grounds for microorganisms, and areas that are not cleaned may cause cross-contamination of subsequent drugs. In most cases, sterile drugs are at a much higher risk of microbial contamination. However, contamination of non-sterile products, such as tablets containing highly toxic active ingredients, is just as severe.
3. The Equipment must comply with the applicable technical rules
Although GMP is legally binding, the specific regulations are vague, especially in technical details. Due to the large number of production processes for drugs and the wide variety of production equipment, it is almost impossible to formulate specific, uniformly applicable information. In addition, as technology develops, GMP requirements are also changing accordingly. Therefore, the following guidelines must be ensured: The Equipment must use the latest technology. From a legal point of view, in the event of a drug liability case (a drug harms a patient), the judge may ask the expert: Does the production equipment meet state of the art at the time?
The question is which technical rules must be followed for various devices, or where to find the actual state of the art. Indicative and non-binding pharmacopeias or regulatory agency guidelines may provide relevant information. It is usually recommended to know the relevant ISO standards or VDI (in Germany) guidelines.
4. The Equipment must be suitable for its intended use
This is one of the most critical requirements. This means that the drug manufactured using this equipment meets the pre-defined quality standards and has the desired medical effect (meaning demonstrated in clinical studies).
The Equipment must prove its suitability through “confirmation”, which plays an important role in process validation. Specific confirmation is related to specific products. A device suitable for drug A is not automatically suitable for drug B. This suitability must be demonstrated through revalidation. Pharmaceutical companies must prove that the device is suitable for its intended purpose or use through “validation.” The more complex the drug production, the more customized the device. Therefore, it is easier to validate a ready-made generic device than a customized device because the test method is the same and the validation document can be prepared by copying and pasting.
5. The device must meet the application document requirements
The documents here refer to those submitted to the licensing authority when the drug applies for marketing authorization. Every drug needs marketing authorization before it can be put on the market. In addition to providing the results of clinical, pharmacological, and toxicological studies, the application for marketing authorization also includes documents on quality. Contains detailed information about the production process and partial information about the production equipment (including technical drawings of equipment parts or P&ID with all the details, etc.). These documents will become part of the marketing authorization. The pharmaceutical industry is relatively conservative about technological changes because every technological change will raise questions about the above five points. It must be proved during the change process that the change will not cause the device to have an adverse effect on the drug. The relevant QA department always wants to avoid changes to the application documents, because changing the regulatory documents submitted when applying for marketing authorization can be a very expensive and time-consuming matter.