Residue removal in cleanrooms: A regulatory overview

STERIS' Walid El Azab reviews the regulatory documents overseeing cleaning and disinfection, and explains why effective cleaning is required for residue removal

A contamination control strategy should be used to evaluate how effective the cleaning and disinfection programme is; a robust programme prevents microbial and other cross-contamination. 

Cleaning can be performed separately or as a part of the disinfection step, with the main goal of removing residue build-up on the cleanrooms surfaces. These residues are generated from various sources such as:

  • Products, buffers, or media 
  • Human shedding (e.g. skin flakes and particle)
  • Equipment and item particle generation 
  • Chemical residues after their applications on the surfaces (e.g. floor resurfacing compounds, detergents, disinfectants, sporicides, and sanitisers)
  • Viable particles such as microorganisms or  cellular debris (e.g. endotoxins/pyrogens)

Regulations for residue removal

The extracts below show that adequate cleaning and disinfection can only be ensured if the premises’ layout, flows, equipment and material design are chosen to minimise the risk of cross-contamination and build-up of residues:

a. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines

(Note that the PI009-14 GMP guideline is  equivalent in some regards to the Eudralex Volume 4 requirements)

  • a.1. Annex 1, Manufacture of Sterile Medicinal Products, 2008:
  • 46. In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimise the shedding or accumulation of particles or microorganisms and to permit the repeated application of cleaning agents, and disinfectants where used.
  • 47. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment.
  • a.2. Annex 1, Manufacture of Sterile Medicinal Products, draft 2017: (Note that article 5.4 of the draft guideline is the same as article 46 of Annex 1).
  • “5.31…Cleaning programs should be effective in the removal of disinfectant residues.”
  • a.3. Part IV, Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (ATMP), 2018: (Note that article 4.31 of the ATMP guideline is the same wording as article 46 of Annex 1).
  • 4.42. Appropriate cleaning/sanitation of clean areas is essential, including the removal of residual cleaning agents/disinfectants.
  • a.4. Part I, Chapter 3, Premise and Equipment, 2015: “… Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt and, in general, any adverse effect on the quality of products”.

b. FDA, Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, 2004

  • “Cleanrooms are normally designed as functional units with specific purposes. The materials of construction of cleanrooms ensure ease of cleaning and sanitising.”

c. WHO Technical Report Series

  • c.1. No. 986, 2014, Annex 2: (Note that the article 12.2 is equivalent to the extract referred in the EU GMP Chapter 3)
  • “12.2 The layout and design of premises must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and in general, any adverse effect on the quality.” 
  • c.2. No. 961, 2011, Annex 6: (Note that the article 11.2 is equivalent to article 46 of the EU GMP Annex 1).
  • “3.1 … Interactions between different cleaning materials should be validated. Appropriate cleaning validation should be carried out to ensure disinfectant residuals can be detected and are removed by the cleaning process.”

d. Canada, GUI-0001 - Good manufacturing practices guide for drug products, 2018

  • “The premises in which a lot or batch of a drug is fabricated, packaged/labelled or stored shall be designed, constructed and maintained in a manner that permits the operations therein to be performed under clean, (a) sanitary and orderly conditions; permits the effective cleaning of all surfaces therein; and (b) prevents the contamination of the drug and the addition of (c) extraneous material to the drug.”

e. Japan - Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing

  • “The disinfection of the manufacturing environment should not proceed prior to cleaning, as a rule. If there are any locations in the environment where cleaning agents may reside after cleaning, the cleaning agents should be verified not to impair the efficiency of disinfectants.”

f. ANVISA Resolution, Technical Regulation of Good Manufacturing Practices of Drugs – RDC n.17, 2010

  • “Article 402. In clean areas, all exposed surfaces shall be smooth, impervious, to minimise the accumulation or release of particles or microorganisms, allowing the repeated application of cleaning agents and disinfectants, where appropriate.”

Based on these regulations, residue build-up comes from various sources that may impair the efficacy of cleaning and disinfection procedures. Effective cleaning and disinfection prevents unacceptable levels of viable (e.g. microbial) or non-viable (e.g. particle, residue) contamination.

Residue removal programme

The removal of residue build-up is generally performed by a cleaning step that requires a mechanical action. The step also prepares the surface for disinfection by reducing levels of particles, fibres, microorganisms, disinfectants, product residues, and other residues. It can be performed separately (two steps) or as a part of the disinfection step (one step).

Residue removal frequency depends on build-up over time, and is typically set based on a visual inspection. The cleaning and disinfection procedure should be based on the nature and the amount of residue, the cleaning agent if used, and the formulation of the disinfecting agents. 

The cleaning agent (e.g. water or detergent) to use would depend on the type and amount of residue before the disinfection step.

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The following options may be considered based on the cleaning and disinfectant procedure in place:

  • For disinfectants that are not effective as a  cleaner or without surfactants in their formulation, the removal of residue build-up should be performed using a cleaning agent before disinfection. The cleaning agent may be rinsed at a justified frequency if it is known to leave residue.
  • When using disinfectants that are effective  cleaners or contain effective surfactants:
    • If the amount of residue build-up before  cleaning and disinfection is low, then the disinfecting agent is capable of cleaning while disinfecting. The rinse frequency may be set based on the ability of the visual observation of disinfectant residue build-up.
    • If the tenacity and the amount of residue build-up before cleaning and disinfection is high, then the surface may need to be cleaned before disinfection. The removal of residue build-up should be performed using a cleaning agent. The cleaning agent may be rinsed at a justified frequency if it is known to leave residue.

Understanding the factors that generate residue is crucial as they vary widely in both origin and impact. Residue from many possible sources build up over time if adequate removal is not included in your programme.

Effective cleaning is required, but cleaning agents may leave residue on the surface too; hence a rinse step should also be included in your cleaning programme. The rinsing frequency should be adjusted based on the visibility of the residue your process and cleaning programme leave on the surface. Rinsing will typically require only water (WFI or PW) or 70% isopropanol to achieve visually clean surfaces. 

N.B. This article is featured in the January 2020 issue of Cleanroom Technology. Subscribe today and get your print copy!

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