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What is Sterile Manufacturing?

The pharmaceutical industry places great emphasis on hygiene, and with good reason. There is no scope for error, no space for the slightest contamination, no potential risk permissible when people’s health is at stake. Whether they are vaccines, injectable drugs, biologics, lyophilized (freeze-dried) powders, eye drops, nasal sprays or other parenterals – it is critical that they are manufactured in sterile conditions so that patients are not exposing themselves to any unwanted pathogens due to compromises in the sterile manufacturing process. What is sterile manufacturing, you ask?

There are many different approaches and methods to sterile manufacturing, and we’re here to break them down for you.

What is sterile manufacturing?

As a pharmaceutical manufacturer, you want your products to have the highest level of purity and safety. This means avoiding contamination of any sort – visible or invisible – which might impact the health of those using your products. Sterile manufacturing involves ensuring that your pharma products are free of microbial contamination, particulate matter and impurities of any other kind.

Aseptic manufacturing vs Terminal sterilisation: what’s the difference?

When people say “sterile manufacture” in common parlance, they are often referring generally to the processes involved in creating a sterile product. People often use sterile manufacturing and aseptic manufacturing interchangeably when, in effect, they are different approaches to creating a sterile product. The steps involved, level of complexity, and products they are used for vary greatly.

Aseptic manufacturing processes are conducted in a manner that ensures that no microbial or other contamination is allowed to interfere at any point in the process, from storage and formulation to filling and packaging.

On the other hand, sterile manufacturing (also referred to as terminal sterilisation) deals with the final product of the pharmaceutical process.

Aseptic manufacturing is used in the production of biologics, vaccines, injectables, cancer drugs, and any liquid or spray meant for application in the ears, eyes and nose.

Other pharmaceutical products like intravenous (IV) bag solutions including dextrose and saline, small molecule drugs and diluent solutions which can tolerate sterilisation by heat or radiation usually undergo terminal sterilisation.

Many steps are involved in aseptic manufacturing, each adding to the complexity of the entire process. Manufacturers carry out aseptic processes in specialised facilities called cleanrooms, with support from highly trained personnel who are methodical in every step of the process – they can’t afford it any other way. Whether it is making the formulation, storing or filling it, inspecting, labelling or packaging it, extremely skilled personnel are employed to ensure compliance with requirements because even the smallest of errors can lead to health risks, delays in production timelines, increased costs, or loss of product.

When compared to aseptic manufacturing, sterile manufacturing or terminal sterilisation is relatively simple, though still indispensable for certain drugs. It is easier in terms of effort and easier on the pocket. The level of risk involved is also slightly lower since the process comprises fewer steps. Here, too, technically skilled professionals operating the procedures with care and attention to detail make all the difference. However, according to FDA guidelines, this method of sterile manufacture is appropriate only for any drug that is able to withstand heat or radiation sterilization with no adverse impact on the quality, efficacy and safety of the drug. For everything else, producers should rely on aseptic methods in their sterile manufacturing process.

As easy as ABC? Not really!

The challenges involved in sterile manufacturing are diverse. The interactions of the pharmaceutical raw materials and products with container, air, personnel and packaging are complex; they require a delicate balance of environmental conditions. As such, maintaining the sterility of the product is no easy feat.

To begin with, in sterile manufacturing processes – specifically in aseptic manufacture – each piece of equipment and each packaging component that interacts with the pharmaceutical product needs to be individually sterilized. The room must be monitored regularly to make sure that optimum atmospheric conditions are maintained throughout the lifecycle of the drug production process. Personnel must not only be technically skilled, but must also be equipped with the right protective garments to avoid shedding of any particles in the designated space.

Coming specifically to equipment and facilities, specialised machinery which can support the required ISO 5/Class A conditions are ideal. These must be located in a clean room, a space that is monitored constantly to detect any changes in air quality, particulate matter level, pressure, temperature, humidity and microbial presence that might hamper sterile manufacturing of a drug or vaccine. These facilities should meet the sanitary requirements that make up Current Good Manufacturing Practices (CGMP).

Clean rooms have different classifications depending on the product they are designed to cater to. Here, not only are the pharmaceutical product and equipment, but also the personnel involved are monitored for their microbial and particulate burden to meet defined standards. Air filters clear out the air of any contamination, surfaces are routinely subject to deep cleaning to do away with microbial growth, and the protective equipment of personnel go through cleaning procedures which ensure sterility.

Potential sources of contamination

Contamination can occur from a number of sources, one of the most significant being cross-contamination, in which bacteria or other pathogens from another area of the manufacturing process or from outside the production facility inadvertently make their way into an area that should ideally involve sterile manufacture. Such microbial or particulate transfers can occur due to something as simple as inflow of unfiltered air which would bring with it its microbial ecosystem. Human error can also cause such safety issues which may ultimately harm not just users of the drugs, but also the workers involved in its production.

Good Manufacturing Practices

FDA-defined Current Good Manufacturing Practice standards encompass guidelines for containers, equipment, buildings and personnel, some of which we will have a look at here.

The buildings, rooms and equipment within which sterile manufacturing occurs should be designed specifically to prevent contamination. The FDA recommends that facilities for the sterile manufacture of products have:

  • Easily cleanable surfaces including smooth and hard walls, floors and ceilings
  • Equipment made of materials that will not react with or absorb drug products to alter their quality, safety or purity
  • Controls for humidity, temperature, air pressure, dust and microorganisms
  • Air supply which is filtered through high-efficiency particulate air filters under positive pressure
  • A system for disinfecting the space and equipment, and producing aseptic conditions
  • A positive pressure differential of at least 10 to 15 Pascals relative to adjacent rooms so that strong outward airflow minimises entry of air from non-sterile rooms
  • Environmental monitoring systems which assess compliance with standards on a routine basis

As for the vessels or containers which hold the raw materials or finished pharma products, CGMP dictate that:

  • Preparation containers and closures should be rendered sterile before use
  • Written procedures should be instituted to specify frequency of (re)validation of such procedures
  • The procedures should also indicate the time limits for holding sterile, depyrogenated containers
  • High purity water should be used in the wash and rinse cycle of sterile manufacturing containers so as not to contaminate them
  • Closure systems must prevent the penetration of microorganisms into the container

Finally, when it comes to personnel, the risks are highest due to manual errors, movement in and out of facilities, and potential lapses of judgement. The less a process is automated, the more human intervention is required, and the higher the risks of contamination are. CGMP requirements when it comes to personnel include:

  • Contacting sterile materials solely with sterile instruments
  • Moving carefully, slowly and deliberately in the facility as rapid movements can create turbulence by disrupting the unidirectional airflow maintained to protect sterile equipment and containers
  • Maintaining proper gown control to prevent contamination risk to it
  • Monitoring surface samples on personnel’s gloves and gowns, especially in processes that are more labour intensive

These are only a few of the considerations you, as a pharma producer, should keep in mind while setting up a sterile manufacturing process. A manufacturer keen on producing the safest, most efficient products will deeply study not just CGMP recommendations on sterile manufacturing, but also the properties of the products they want to manufacture. After all, each pharmaceutical product has different requirements to maintain its purity and efficacy.

Inadequate CGMP conditions stand to threaten human life and health. As a dependable pharmaceutical manufacturer, you don’t want to compromise on the safety of your products. Use these principles and standards to further guide your study into exactly what is sterile manufacturing when it comes to the specific drugs or vaccines that you produce.

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