Basic Cleaning and Sanitation Practices in Pharmaceuticals Manufacturing
For almost 20 years, it has been a basic GMP requirement that all cleaning steps in a pharmaceutical plant be documented accurately, and also validated to prove they work. Once the steps are validated, employees must only follow the approved procedure.
According to UDFDA, Equipment – Subpart D Sec. 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, [he following:
(1) Assignment of responsibility for cleaning and maintaining equipment;
(2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;
(3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipment from contamination prior to use;
(6) Inspection of equipment for cleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in 211.180 and 211.182.
Some kinds of contamination are often difficult to detect by physical inspection. The claim: “It looks clean, therefore it must be clean” is not necessarily true. Laboratory testing for potential contaminants is generally not practical, economical, nor reliable.
What is cleaning?
Cleaning is the removal of visible and microscopic contamination by dirt, extraneous mailer, or product residues by mechanical or physical means. Cleaning is usually followed first by visual inspection, and then by laboratory testing to verify that the cleaning continues to be effective.
Effective cleaning usually requires the use of cleaning agents such as detergents and solvents, which are used under specified conditions of pH, temperature, time and solvent concentration.
A concern with cleaning is whether or not the cleaning agent itself will have a negative effect on the life of the equipment or on the quality of the product.
What is sanitation?
Sanitation is the reduction of microbiological contamination. It is usually achieved by the use of chemicals.
However, it can also be achieved by hearing and even vigorous mechanical action, such as scrubbing.
(Note: Cleaning may result in a partial reduction of the microbial load.)
If sanitizing chemicals are used, it may be necessary to remove the sanitizers’ residues by further cleaning. It is therefore very important to use the specified amount of sanitizing agent.
There are several factors that determine how effective sanitizing will be. These include:
- The number and types of microbes
- The type of material containing the microbes
- The concentration, temperature, and pH of the sanitizing agent
- The length of time you sanitize for.
Note: It is impossible to sanitize a dirty surface. The surfaces must first be thoroughly cleaned.
Cleaning and sanitation are both needed to reduce potential contamination. Contamination could negatively impact the end product if it is present in the manufacturing facility or on production equipment.
- Chemical contamination
- Environmental contamination
- Biological contamination
For sterile products, production must be done cleanrooms protected by High Efficiency Particulate Air (HEPA) air filters. Cleanroom requirements are very strict in these areas and are usually associated with positive room pressures (overpressure) to protect the areas from external airborne contamination. Usually 99.97% of all airborne particles above 0.5 microns are excluded by the HEPA filters.
Cross Contamination in Potent Products
The prevention of cross-contamination is particularly important when the factory produces products such as steroids, hormones, antibiotics, cytotoxic products and some potentially pathological biological materials.
These materials, even in minute amounts, may have a significant effect on the body, and it is important to isolate them from the environment during manufacture, and remove their residues from equipment during cleaning.
If you manufacture any of these products, ensure that you are fully aware of the rules for handling and cleaning. Wear the protective gear provided.
Chemical contamination occurs when product becomes contaminated with other materials or products. This can potentially occur when different products are processed in the same equipment, or when materials such as cleaning agents and lubricants come into contact with products or product surfaces.
The way to avoid chemical contamination is by following written cleaning procedures exactly. Often the steps and conditions in the procedures have been validated to ensure they are effective.
Changing the steps or conditions may make the cleaning ineffective.
Different areas of manufacturing within the facility carry different levels of contamination risk to the product.
In areas where product is exposed to the environment, for example, in the dispensary, formulation areas, and bottle filling rooms, there is a higher risk of contamination. Air control is required (usually filtered), and frequent cleaning of the facility and environmental monitoring are recommended.
In other areas, such as in secondary packaging or in material storage areas, the product isn’t exposed to the environment, so there is a lower risk of contamination. Less environmental air control is necessary, the frequency of cleaning is reduced, and environmental monitoring is minimal.
Visual Evidence of Contamination
Visual inspection of products is easy and inexpensive, but it is often labor-intensive and unreliable. Although obvious contaminants can be seen, there may be microscopic contaminants in the product, such as microbial, particulate, and product chemical residues, which are all difficult and expensive to detect once they are inside product.
The aim in good cleaning and sanitation practices is to prevent contamination arising in the first place, rather than try to detect it once it is present.
“Biological contamination” refers to contamination by bacteria, yeasts, moulds, viruses, or any other micro-organisms that may be present in product. This also can include residues from dead micro-organisms or endotoxins, which can contaminate injectable products.
The origins of biological contamination are varied, but include the environment, personnel, raw materials, contaminated water, and poorly cleaned or wet equipment.
While cleaning reduces biological contamination, sanitizing agents play an important role in killing micro-organisms.
Types of sanitizing agents
Different sanitizing agents will be effective only in certain circumstances.
Proper use results in bacteria reduction of >99.9% if used on pre-cleaned surfaces. Pre-cleaning is always required in order to reduce bioload and dirt.
Proper use results in 100% kill of vegetative bacteria, target viruses and target fungi. Pre-cleaning may or may not be required, but it is considered a pre-requisite.
Proper use results in 100% kill of all micro-organisms, including bacterial spores. Pre-cleaning is always required in order to reduce bioload and dirt.
Proper use results in 100% kill of all bacterial spores.
Sterilization Vs Sanitation
Sterilization means the total elimination of any living organisms, usually by heat or chemical means, of any living organisms.
Sanitation means the reduction in microbial load (the bio burden) by chemical means. The end result of sanitation does not guarantee the complete absence of micro-organisms.
The majority of chemical and physical agents in use will clean and sanitize and/or disinfect but not sterilize.
Common Sanitizers for GMP
- 70% v/v alcohol (for surfaces)
- Quaternary ammonium compounds (QUATs)
- Sporicides (for killing spores)
- Chlorines (such as hypochlorite)
- Hydrogen peroxide/peracetic acids
- Sodium hydroxide (cleaning & partial sanitizing)
One should be familiar with their company agents and only use approved agents in the nominated strengths.
GMP rules and cleaning
The GMP rules are very explicit regarding the requirement to clean and sanitize equipment and the manufacturing facility.
Since most residues cannot be seen nor reliably tested for, the company’s standard procedures and cleaning records are relied upon as evidence of cleaning.
GMP requires the cleaning procedures to be fully documented in written procedures. These procedures are initially validated (shown to be effective) specifically for an item of equipment or an area.
Once validated, the procedures are then published and used.
All cleaning procedures should be validated (shown to be effective) under specific conditions of use. These conditions of use are specified in the written procedure.
If employees alter the conditions of use, the cleaning methods may be “invalidated” and may not be effective. For example, it would seem logical that adding more sanitizer than the procedure requires would make cleaning faster or better. This is not always the case. Adding additional sanitizer may alter the pH of the cleaning agent and make it less effective.
The relevant GMP rules are to only clean under validated conditions, and to follow procedures exactly.
The written procedures describe the required conditions under which cleaning is optimal. These conditions may include a range of the following:
- Strength of the cleaning or sanitizing agent (e.g. 2.0% v/v)
- The type of water or solvent to be used
- The pH of the cleaning agent
- The temperature of the water to be used
- How much to dismantle equipment before cleaning commences
- The contact or residence time for the sanitizing agent on the surface
- What agents to use to clean off the sanitizing agent
- What standard of water to use in the final rinse (GMP, for example, requires purified or water for injection as the final rinse)
One essential GMP rule is the keeping of detailed cleaning records. Cleaning records provide not only proof that cleaning took place, but also provide evidence of the cleaning outcomes, for example, that the surfaces are visually clean, or the results of rinse water tests. The records must also identify who did the cleaning and when, and must be signed.
For automatic cleaning procedures such as clean in place (CIP), the cycle conditions are usually automatically monitored and the conditions recorded. Cycle conditions may include the temperature, flow rate, time, concentration of solvent, and solvent agitation time. Often CIP systems have alarms when something goes wrong.
The completed and signed records should be attached to the records, since they provide the only real evidence that cleaning has occurred.
What must be cleaned?
- The facility must be regularly cleaned. Particular emphasis is placed on areas or rooms where product is processed.
- Particular emphasis is placed on the effective cleaning of all equipment in contact with product, and must be cleaned according to validated and detailed procedures.
- All equipment in processing areas not in contact with product needs regular cleaning in order to prevent buildup of dust and dirt.
- The inside of the factory should be regularly cleaned, but particular attention should be paid to the processing and storage rooms. The floors, surfaces, benches, walls and ceilings should undergo cleaning at defined intervals.
- Cleaning and sanitation also applies to any equipment that is in contact with the product during manufacture, such as production and packaging equipment, transfer lines and tanks, and storage containers and drums.
One of the most overlooked reasons for cleaning is to protect yourself.
Chemicals may cause adverse reactions in people if they are continuously exposed to them.
Regular and thorough cleaning, wearing protective garments, and abiding by correct handling procedures eliminate this problem.
- Wearing hair nets.
- Wearing protective gloves and face masks.
- Wearing disposable gowns.
- Checking the procedure to verify if the chemical residues may need special handling.