GMP module 03 - Cleaning Practices in GMP

Outcome of the Module:

Cleaning practices and sanitation programs are an important part of GMP, as they protect products from environmental contamination and cross-contamination with other materials or product. These programs are also designed to protect us from the effects of hazardous materials.

At the end of the module, you will be able to:

  • Define the meaning of the words “cleaning” and “sanitation”
  • Recognize why you need to clean before you sanitize
  • Identify the GMP requirements for documenting cleaning and sanitizing activities
  • Explain the reasons why you must use only approved cleaning and sanitizing materials
  • Explain why cleaning and sanitation prevents product contamination

Part I: Cleaning and Sanitation Defined

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.

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

 

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.

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.

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

Part II: Facility Cleaning

Most production facilities are multi-use, that is, on any given day, different products will be simultaneously processed, but never in the same rooms. The primary means of preventing cross-contamination in multi-use facilities are the air controls (sometimes called HVAC).

Room pressures serve a couple of functions. They contain dust within a room, and prevent the dust from getting into other rooms (negative pressure). Room pressures also exclude outside air containing dust, dirt and microbial particles from entering a facility (positive pressure). If these pressures are lost, then there is potential risk of contamination. No amount of laboratory testing could overcome this problem, since the laboratory cannot possibly devise tests for all possible contaminants.

Cleaning is a technical task. When you are cleaning, it is important to:

  • Wear the same clothing as in the processing areas.
  • Make sure you are trained in all written cleaning procedures,
  • Use only specified cleaning agents,
  • Maintain appropriate cleaning records.

 

Part III: Equipment Cleaning

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. 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.

 

Part IV: Cleaning Records

One of the most stated rules in GMP is “You cannot test quality into products. You must build it in at each step in the entire process.” This statement is especially true with regard to effective cleaning and prevention of cross-contamination in products. No amount of laboratory testing can substitute for prevention. The cleaning records, if completed correctly, should verify that each item of equipment in contact with product was cleaned:

  • Using validated written procedures
  • By trained employees
  • Prior to use and stored correctly as per its status tag

 

There must be evidence, via inspection and monitoring records, that the equipment was clean and free from contaminants when processing commenced. It also must be recorded what previous product was processed in the equipment prior to the current batch.

Part V: Clean-in-Place (CIP) Systems

Many facilities use automated cleaning processes known as “Clean-in-Place” (CIP) systems. CIP systems rely on both chemical removal and physical agitation of the pipes, valves and tanks, rather than just physical removal of residues.

The success of CIP systems is determined in their design, installation and commissioning/validation. The design must ensure that there are no “dead legs” (areas where cleaning solution cannot penetrate) and must facilitate the complete rinsing of any residues. The CIP system may be “recirculating” or a “once-through” design. Both systems must be controlled and alarmed so that malfunctions are detected and the system is only considered to be clean after a totally successful cleaning cycle.

As with manual equipment cleaning. CIP systems must be validated to ensure that the previous product has been removed, there is no residual cleaning agent left after cleaning, and the microbial population has been reduced to a safe and acceptable level.

Conclusion:

Cleaning and sanitation practices may compromise product quality by contamination with other products, cleaning agents, and micro-organisms. There are many factors which may affect the effectiveness of cleaning, for example;

  • The type, strength, volume, and concentration of the cleaning agent
  • The time needed for soaking, cleaning, and rinsing

 

Cleaning and sanitation is a technical function requiring diligence, competence, and an awareness of the effect that poor cleaning and sanitation can have on the quality of the final product. So:

  • Wear the correct protective clothing when cleaning
  • Use status tags to identify the cleaning status of equipment.
  • Use only approved cleaning agents.
  • Clean cleaning equipment regularly, inspect equipment after cleaning and again before reuse.
  • Follow standard cleaning procedures exactly.
  • Maintain records of cleaning.

 

Cleaning procedures have been written and validated to achieve the best possible results. If you notice anything abnormal report it to supervision.

Cleanrooms and cross-contamination

Online Quiz:

  • Number of questions: 10
  • No time limit
  • Allow you save and finish at a later date
  • Allow you to go back and change your answer
  • Attempting each question is mandatory
  • Pass mark at and above 70%
  • Print results and certificates
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