FDA Cleanroom Facilities & Equipment: cGMP Requirements

FDA Cleanroom Facilities-&-Equipment - cGMP Requirements

The FDA has set forth requirements for compounding pharmacies and other facilities involved in the production or handling of food and drugs. The chief purpose of this is to prevent contamination and avoid incidents such as contaminated medication from the New England Compounding Center.

As a result, the Food and Drug Administration (FDA) has taken over as primary regulatory body of the compounding pharmacies, dividing the pharmacies into 503A and 503B facilities.

When trying to abide by U.S. Food and Drug Administration standards, it’s vital to know the regulations and the details contained therein. Contaminants can be introduced during every step of production so make sure your facility has a good understanding of cGMP Requirements.

Understanding the Regulations

Requirements for clean rooms are more than just generic or general standards and practices. They’re actually part of a regulated set of rules regarding good manufacturing practices. Current Good Manufacturing Practices or cGMP regulations involve the manufacture of biological products.

These products and drugs produced by manufacturers are regulated by the Code of Federal Regulations. The cGMP for Finished Pharmaceuticals provide information about clean rooms from 21 CFR 600 through CFR 680. These give important requirements for biological products.

The FDA has regulations that regard compliance. Regulations specifically about drug products supersede more general CFR 210 and CFR 211 regulations.

Cleanroom Facility

There are some strict environmental controls that start with the planning and construction of any clean room. It’s vital to have clean air standards in your clean room. If you don’t start by building for a clean air system using the right filters, it’s hard to achieve a clean room.

The FDA describes a cleanroom as an isolated environment, strictly controlled with respect to: Airborne particles of viable and non-viable nature, Temperature, Humidity, Air pressure, Air flow, Air motion, and Lighting.

There should be a monitoring system for your clean room. A separate and adequately-sized room to control humidity, air pressure, temperature, and dust should also have the ability to control microorganisms.

There are regulations requiring that you use an air filtration system. Ensure that you follow written procedures to prevent contamination by cleaning and sanitizing surfaces and equipment. This is the only way to ensure that you achieve the standards of cleanliness required for a clean room.

Aseptic processing facilities will include, as appropriate:

  1. Easily cleanable floors, wall, and ceilings of smooth, hard surfaces
  2. Temperature and humidity controls
  • An air supply filtered through high-efficiency particulate air filters (HEPA) under positive pressure, regardless of whether flow is laminar or nonlaminar

Maintaining Clean Air Levels with HEPA Filters

Refer to ISO 14644 for instructions for collecting air samples to measure particles. This standard will dictate the concentration of air particles. There are specific sizes and thresholds for clean air that should be maintained.

Air samples must be taken during different occupancy states. There should be a sample right after your room is built, before you use it. There should also be tests taken when the room is being unused as well as when it’s operational.

The maximum limits for concentration of particulates in the air is set via ISO classes 1-9. Maximum limits are set by occupancy, size of the room, and the concentration of the room.

The following is a summery from the document Regulatory Education for Industry (REdI): Focus on CGMPs & FDA Inspections, Facilities & Equipment: CGMP Requirements

Efficiency Testing of HEPA Filters

  • HEPA filters generally tested for efficiency at the filter manufacturing site using a thermally generated dioctylphalate ( DOP) aerosol
  • Challenge is a homogeneous, monodispersed aerosol with a particle size of 0.3 micrometers
  • Penetration of DOP through filter should not exceed .03% (Note: 100% – .03% = 99.97% efficiency)

Integrity Testing of HEPA Filters

  • A similar test used for the verification of filter integrity (leak testing or pinhole detection)
  • Includes cold DOP, DEHS, Emery 3000 POA leak test
  • Test differs from efficiency test in the complexity of the aerosol generator and portability of the photometer employed

Integrity Testing of HEPA Filters – Cold DOP

  • Aerosol generator used to produce a polydispersed aerosol containing a range of particles (0.1 – 3 micron) that is introduced upstream of the filter bank while in operation
  • Downstream side of filter is scanned with optical measuring device, usually a light scattering photometer
  • If pinhole leaks are present, particles pass through filter and are detected by optical device

Pressure Differential Control

  • Pressurization used to prevent cross contamination between environments and ingress of contaminants into production areas from adjacent areas
  • Pressure gradients established to provide critical environments with higher pressures than less critical areas
  • Sweeps contaminants away from work surface area
  • Provides pressure cascade

High pressure areas receive more air input and less air exhaust

Difference in air pressure between areas should be adequate to maintain desired direction of air flow

Pressure differentials should be measured with doors opened and closed

Positive air pressure used to prevent the ingress of contaminants from less clean areas

  • Cleanroom man and materials entry from adjacent clean corridor or clean area

Negative air pressure effective in containing or preventing dispersion of sensitive or highly toxic materials

Cleaning Validation

Clean validation begins with, of course, the cleaning procedure itself. An overview of the process includes:

  • Objective of the cleaning process
  • Equipment design
  • Cleaning procedures and documentation
  • Detergents/Cleaning agents
  • Validation protocol
  • Sampling
  • Analytical methods
  • Establishing limits
  • Cleaning of chemical residues and micro

Read more from the source: https://www.fda.gov/media/92841/download