Control of Microorganisms in Pharmaceuticals Production Environments

Micro-organisms are mostly killed by exposure to heat above 55 – 60°C for periods of time. The heat breaks down the cell wall, which kills the micro-organism. The cell walls of spores, however, are resistant to anything but high heat.

Similarly, alcohol is a good general sanitizing agent, but there are some micro-organisms that are not killed by alcohol (such as spores).

A combination of heat and alcohol provides two methods of sanitizing. Of course, sanitation will only be effective if a validated procedure is followed. Pay particular attention to:

  • Pre-cleaning to remove most of the chemical residues and bio burden
  • The length of time the heat and sanitizing agents are applied for: too short an exposure time will be less effective.

Some micro-organisms are of particular concern in certain dose forms.

Objectionable organisms are organisms that shouldn’t be present in a product, because of:

  • Product degradant on, making products ineffective
  • Consumer safety, as products could become health risks

Ideal Microbial Limits:

The significance of micro-organisms in non-sterile pharmaceutical products should be evaluated by the manufacturer in terms of the following:

  • Use of the product (topical or oral)
  • Nature of the product (supports/inhibits growth)
  • Potential hazard to the user (children/sick/old)

It is therefore very difficult to set hard and fast regulatory limits for micro-organisms, except for specific products.

Microbial Controls in Laboratory:

  • It would be virtually impossible to completely validate test procedures for every organism that may be objectionable. However, it is a good practice to assure that inhibitory substances in samples are neutralized.
  • For products such as topicals, inhalants, or nasal solutions where there is a major concern for microbiological contamination, isolates from plate counts, as well as enrichment testing, should be identified.
  • It is recognized that pseudomonads are objectionable if found in a topical product or nasal solution in any numbers. There are no test methods provided in the USP that will enable the identification of the presence of this micro-organism.

How to Minimize Microorganism:

We cannot eliminate micro-organisms. But we can minimize their numbers, or exclude them from our manufacturing following lists a number of methods we use to minimize micro-organisms:

  • Control the manufacturing environment
  • Wear protective clothing
  • Implement cleaning and sanitation programs
  • Keep equipment clean and dry
  • Maintain room pressures by keeping doors closed
  • Maintain a high standard of personal hygiene

Critical microbial control issues:

The challenge to the industry is to minimize or, as with sterile products, totally exclude or destroy micro-organisms from the products being manufactured.

Critical microbial control issues arise during different stages of the manufacturing process. These issues can arise in:

  • Starting materials control
  • Production equipment control
  • Water and other critical services control
  • Environmental control
  • Personnel control

Control of Microorganisms in Manufacturing:

  • Microbiological testing is far from absolute.
  • Negative test results may merely indicate insensitivity of the test.
  • Microbiological contamination is not evenly dispersed throughout a lot or sample of product.
  • Finding a contaminant in one sample and not in another does not discount the findings of the initial sample results.
  • Other organisms may mask the presence of certain organisms when identification procedures are performed.

Control in the Starting Materials:

Starting materials must always be handled and stored in a manner to prevent contamination. Some important handling and storage rules include:

  • Store starting materials clean, dry, and if necessary, cold.
  • Store starting materials off the ground, and under cover.
  • Always keep containers sealed when not in use.
  • Be alert to damaged packages.
  • Never use dirty or wet sampling or measuring equipment.

Starting materials themselves may contain potentially contaminating micro-organisms. QC testing takes into consideration the origin of the mater al, intended usage, and probability of microbial contamination. Suppliers of starting materials should also be audited, either by extended QC testing or by site inspections.

Control in the Equipment:

Equipment con also be a source of contamination, so there should be controls in place that ensure equipment is kept dry and sanitary.

Focus microbial monitoring on “at-risk” equipment, such as on topicals and liquids lines, as well as product contact surfaces.

Monitor after cleaning or before re-use.

Periodically identify the bio load to check for objectionable organisms, and build up a profile of them.

Control of pharmaceutical water:

Water is a key ingredient of many pharmaceutical products, however, it is an essential ingredient in promoting microbial growth.

Therefore, its microbial “‘cleanliness'” is critical within pharmaceutical companies.

Pharmaceutical water is used in two main ways: as part of product formulation, and as a cleaning agent for equipment. 

Purified water:

This water is intended for the formulation of non-sterile products and final rinsing of equipment after cleaning. Purified water is used extensively in the plant. It is monitored by Quality Control, and has specified limits for bio burden.

These limits are not failure limits, but rather indicate when action should be taken to correct the system.

Action limit     100 cfu/mL
Warning limit 10 cfu/mL
Target limit     1 cfu/mL

Water for injection (WFI):

This water is intended for the formulation of parenteral, dialysis, or inhalant products. It should be prepared by distillation or reverse osmosis.

WFI is usually held under high temperature (> 80°C) to ensure that there is no chance of microbial growth. WFI is monitored by QC, usually daily, to ensure that the system remains bio burden- and endotoxin-free.

Typical limits for WFI are:

Target       no organisms / 100 mL

Action   < 10 organisms / 100 mL and <0.25 endotoxin units/mL

*** The presence of any endotoxin in WFI is usually a major concern.

Microbial Control Issues in Water Systems:

These following concerns are based on the product types being manufactured:

  • For topicals and inhalants, there must be no presence of pseudomonads in the water testing profile.
  • Systems must be able to be regularly sanitised. Each unit within a water system may have different sanitation conditions.
  • Manufacturers need active change control and maintenance programs.
  • The QC test program should carefully document:
  • Sample points and timing “worst-case”
  • Sufficient frequency of testing in order to generate meaningful results
  • Pay attention to the limits and responses to out-of-limits.

Control of the environment:

When products are exposed to the environment, the environment must be controlled. Some ways of achieving environmental control include the implementation of:

  • Air handling systems
  • Designated manufacturing zones
  • Cleaning programs

Air handling systems:

Air handling systems include ways to filter the air, for example, with the use of HEHA (high-efficiency particulate air) filters that trap micro-organisms in the air. The air handling systems should generally maintain positive air pressure relative to the outside environment in order to prevent particles and micro-organisms from entering the facility, and particularly the manufacturing areas.

This is one of the main reasons that all doors should be kept closed. 

Designated manufacturing zones:

There should be designated manufacturing areas at the facility to keep products away from the outside, “non-controlled”, environment.

Within the designated zone, doors and windows should be kept shut, and people and personnel entering the designated zone should change their outer garments.

Cleaning programs:

Cleaning programs at the facility should include keeping manufacturing areas clean and dry at all times, as well as regular checks and periodic cleaning of the air ducts and filters.

In particular, surfaces that may catch dust should be regularly cleaned, such as ledges, door handles, piping, etc. 

Personal hygiene practices:

People are potentially the largest source of micro-organisms, and are the hardest factor to control.

In the pharmaceutical industry, companies should ensure that:

  • Staff wear protective garments (including caps and shoes) that are clean, and are only worn in designated processing areas.
  • Product isn’t handled with bare hands.
  • GMP induction and ongoing GMP training include personal hygiene and sanitation rules.
  • Personnel wash hands after visiting the toilet.
  • Micro-organisms make up more than 50% of the weight of human faeces (approximately 1 trillion/g). Even after washing hands, your skin will again contain over 20,000 microbes per cm2.
  • Airlocks between toilets and production areas
  • Any staff infections are reported to supervisors
  • There are policies in place prohibiting food, cosmetics and jewelry in production areas.

Key points about controlling microorganisms:

  • Micro-organisms are very adaptable, and are found everywhere.
  • Micro-organisms need only small amounts of nutrients and moisture to grow, and they can grow very quickly.
  • Objectionable organisms should not be present in a product because they can reduce the product’s effectiveness and cause possible harm to consumers.
  • Although micro-organisms cannot be necessarily eliminated entirely, manufacturers need to keep micro-organisms at acceptable levels.
  • To reduce the numbers of micro-organisms in the workplace, there must be strict controls in place over the manufacturing environment, starting materials, equipment, pharmaceutical water, the environment, and personal hygiene.
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