Sterile Manufacturing 101

Sterile manufacture represents a higher level of practise and operational art when compared to non sterile GMP. The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved.

Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.

The guidance that must be followed in the area is itself is a mixture of both high level principles and some very specific requirements which can make it hard to read and place into a wider context. At the same time, there is a dedicated at passionate community of professionals that continue to publish new work in the area and drive the field forward. These factors can make the field uninviting and intimidating to new entrants. It is important to remember this is not magic.

I have prepared a interlinked set of notes on the foundational knowledge that is expected within sterile manufacture below in Section 1. Section 2 puts these into practise with worked example production systems for candidate sterile products. Section 3 covers example sterile questions a QP may come across. Finally Section 4 links to curated sources of more detailed information.

Section 1

  1. Microbiological agents and their impact on humans and products

  2. Sterility and Sterilisation?

  3. Sterility assurance levels?

  4. Aseptic Processing vs Terminal Sterilisation?

  5. Why aseptic process?

  6. Regulatory Guidance

  7. Contamination Control Strategy

Section 2 - Underpinning Technologies

  • Facility design expectations

  • Raw material control

  • Material handling and packaging

  • Water systems

    • Purified Water

    • Water for injection

    • Water system validation

  • Clean Utilities

    • Compressed air

    • Process Gases

    • Cooling Systems

  • Cleanroom Operations

  • Sterilisation method

    • Moist heat sterilisation

    • Dry Heat sterilisation

    • Sterilisation by vapour or gas

    • Sterilisation by filtration

    • Solution filtration

    • Gas filtration

    • Filter integrity testing

    • Sterilisation by irradiation

    • Depyrogenation

  • Aseptic processing

    • Aseptic Manufacturing

    • Aseptic Filling

    • Aseptic Process Simulation

3) Building defence in depth.

The bias on keeping contamination out of the product has shaped the way cleanroom and production systems are designed and operated. Despite the vast range of available processing systems and product categories there are a few universal practices and layout systems that industry as a whole adhere to. A graphical representation of some of these is included below

Section 3

Pharmaceutical law and administration

Human Medicines Regulations 2012 and other UK national medicines legislation e.g. SI, and the Veterinary Medicines Regulations, including amendments

European Pharmaceutical Directives