Some Tips of Equipment Cleaning in Pharmaceuticals Manufacturing Plant
The cleaning of equipment, particularly equipment that has been (or will be) in contact with product, is one of the fundamental principles of GMP. It is almost certain that unclean equipment will in some way contaminate the next batch to be processed.
GMP rules worldwide place particular emphasis upon the effective, validated cleaning of all product contact equipment. The GMP rules also require that written procedures be available on how to clean and store such equipment. During storage, it is possible for clean equipment to be re-contaminated if it is exposed to the environment (i.e. not fully covered over).
Another way that equipment can be contaminated on storage is by leaving equipment wet, which would support the growth of microbes.
Prevention of Cross-contamination in Production
Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapors, sprays or organisms from materials and products in process, from residues on equipment, and from operators’ clothing.
Equipment cleaning is critical to product quality. Cleaning is as much as a technical task as formulating, so it requires the same attention to detail and compliance to GMP.
The same principles apply for equipment cleaning as they do for facility cleaning:
- Follow all written cleaning SOPs,
- Maintain records of cleaning.
- Use only those cleaning agents that have been approved by QA.
- Store cleaning equipment in dry conditions, and clean the cleaning equipment regularly.
With equipment, a togging system should identify the equipment cleaning status.
Equipment may have a number of areas where cleaning is difficult or where product residues tend to build up during processing. Move your mouse over the red circles in the diagram to see more information about these trouble spots.
Cleaning of Water Residue in Hoses
A common problem in production areas is the cleanliness of transfer hoses. Transfer hoses can be a major source of microbial contamination if left wet on storage. If a wet hose is reused later, it may then transfer bio burden back into the tank on the first flush through, causing microbial contamination of the next batch.
The specific GMP rules for hoses are:
- After cleaning, ensure that all hoses are detached from the equipment, and fully drained.
- Where possible, store hoses vertically away from wash bays.
- Keep hoses off the floor.
- Periodically sanitize, the hoses to keep them fresh.
- Flush the hoses before use, where possible.
- Where hoses are dedicated to a product, make sure that they are properly identified as such.
Common and dedicated equipment
A common question regarding equipment cleaning is, “Does equipment have to be cleaned if it’s going to be used again for the same product?”
The short answer is yes, however, the depth of cleaning may be different depending on whether or not the following batch is the same strength of the same product, a different strength of the same product, or a different product altogether. Each of these in turn will require more intensive cleaning.
Common equipment is equipment that is used for more than one type of product. Common equipment must be completely cleaned, and sanitized if necessary, before every use, in order to prevent carryover of previous product to the next product.
Dedicated equipment is equipment used to manufacture only one type of product, or for a run of batches (a campaign) of the same formulation. Cleaning requirements for dedicated equipment may be less than those for common equipment, provided the company has documented either the maximum number of batches or the maximum time that can elapse before complete cleaning must be done.
Cleaning validation sets out to prove that the documented cleaning procedure will consistently remove the previous product, remove the cleaning agent, and reduce the microbial population to a safe and acceptable level. Obviously then, when companies handle potent or toxic drugs, equipment cleaning validation becomes a very important.
- Defines the products that can be made in the equipment
- Determines the maximum time allowed before the tank must be cleaned
- Defines the cleaning agent to use, and its correct volume and concentration
- Verifies the temperature of the cleaning process
- Verifies the length of time needed for cleaning.
Cleaning and sanitizing validation verifies that the specific cleaning procedure, under the specific conditions of cleaning described in the procedure, will be effective for a specific range of products in specific equipment. Any changes to these parameters may make the cleaning/sanitizing ineffective.
How was the Practice of Cleaning Validation Started?
The focus on cleaning validation commenced in the early 1990s, when the FDA published the Inspection Guide to Cleaning Validation.
This guidance was prompted by the increased manufacture of potent and new biotechnology products, that had high potency in low concentrations. Clearly then, any of this product left on equipment could cause major contamination risks.
Equipment hold times
1. Post-use / pre-clean:
Once we have completed batch processing, there must be a maximum hold time between post-use and the commencement of cleaning. This is because over time, any residues will start to “bake” onto equipment surfaces and will be much harder to clean off. In addition, bio burden may start to grow.
It is required that procedures nominate and validate maximum allowable hold time. During cleaning, it is required to commence cleaning before the maximum hold time has elapsed.
2. During the cleaning cycle (contact time):
During the cleaning cycle, procedures should specify a minimum hold time for contact of the cleaning agents and sanitizers with equipment surfaces.
This is because in order for cleaning and sanitizing agents to be effective, they must be in contact with the dirt and surface for a period of time.
This contact time is validated.
3. Storage between use
Equipment must be stored dry and protected. GMP rules require that stored equipment must have an “expiry date” or maximum storage time before it needs to undergo re-cleaning.
Most companies have a simple rule: all equipment is inspected thoroughly before use, and any equipment that exceeds its maximum storage hold time is re-cleaned before use.
4. Equipment cleaning status tag
The status of equipment should be apparent at all times, including during storage.
For example, this status tag on a vessel indicates:
- Whether the equipment is clean or requires cleaning
- When the equipment was cleaned or is to be cleaned
- The previous product in the vessel
- When the equipment is due to be re-cleaned
After it is cleaned, the equipment should be stored with a protective cover to prevent contamination on storage.
Regardless of its cleaning status, equipment should always be examined before use to verify that it is clean and suitable for use.
Use of water in equipment sanitation
Water is often used in the cleaning and sanitation of equipment. Therefore, you should know that:
- Water is a good breeding place for micro-organisms.
- Bacteria can double in 15 minutes in water.
- Many water bacteria are harmful and cause consumer sickness or product spoilage.
- To protect the next product from microbial contamination, equipment must be stored dry.
- The final rinse of equipment must be in either purified water or water for injection, so that the surfaces are not re-contaminated after the cleaning cycle is complete.
Cleaning agents and equipment
Cleaning agents and equipment need to be carefully evaluated before they can be used in a manufacturing facility. The choice of cleaning and sanitizing agents is a decision made by QA/QC, so it should be ensured that only QA/QC-approved cleaning agents and equipment be used.
Because of this, GMP rules state that cleaning procedures must indicate the nominated strengths of cleaning agents, and that cleaning agents cannot be changed without approval.
The selection of a cleaning or sanitizing agent is dependent upon:
- The previous product type, for example, a cream or powder
- Compatibility with equipment to be cleaned
- Ease and safety of use
- Ease of removal of residues
- Required contact times on equipment
- The targeted microbial population
Disinfectants must be used in strict accordance with instructions. They should never be topped up, used, or stored without labels and expiry dates.
What is Disinfectant?
Disinfectants are tested for their bactericidal activity against four standard cultures of micro-organisms, namely:
- Pseudomonas aeruginosa
- Staphylococcus aureus
The disinfectant is tested at the manufacturer’s recommended dilution as stated on the product label. The disinfectant dilution is passed or failed according to the extent of growth shown by the challenge bacteria. This is the reason it is very important to make dilutions correctly during use.
A common practice in the industry is to rotate between different sanitizing agents on a regular basis (for example, monthly). The intent of this is to prevent the possible buildup of organisms with resistance to the sanitizing agent being used.
What are the Potential Residues Found in Production?
Some potential residues can include:
- Cleaning agents
- Denatured product
- Denatured excipients
- Heat-denatured residues (with biological products)
- Endotoxins or pyrogens
Cleaning equipment or materials that shed particles, raise dust, produce aerosols or otherwise generate contamination should be avoided where possible. These include compressed air, bristle brushes, fiber-shedding cloths and certain designs of floor-scrubbing machines.
Vacuum or wet cleaning methods are preferred. Vacuum cleaners or polishers should be fitted with fine dust filters.
How to Choose a good Cleaning Tool:
Steel Wool: This is not a good item to use because steel wool sheds fibers and is very abrasive. It can cause fine surface scratches (even in stainless steel) which provides an ideal home from micro-organisms.
Nylon Scourer: Not a good item to use because scourers shed fibers and are very abrasive. They can create line surface scratches which makes cleaning more difficult.
Wooden Brush: This is not a good item to use because wood is hard to dry, and the bristles are hard to clean and may break off. Brushes provide good habitats for microbes because they’re likely to be dirty and wet.
Nylon Brush: This is a good choice because nylon brushes are easier to keep clean and dry and the bristles are soft and non-abrasive.
Non fiber shedding wipes: This is a good choice because they will not shed fibers and non-abrasive. Usually they are used only once so they are very hygienic as well.
Wooden mop: Not a good item to use because wood can splinter and is hard to dry. Wood provides a good habitat for microbes because it is likely to get dirty and wet. String mop heads also shed fibers so they are best avoided.
Wet dirty rag: Not a good item to use because it is wet and dirty. No doubt it contains thousands of micro-organisms.
Steel handled Squeegee mop: A clean squeegee on a squeeze mop with a plastic or metal handle is an effective cleaning item.