CLEANING AND DISINFECTION - A RISK BASED VS AN ARBITRAY APPROACH - PART I
Cleaning and microbial contamination control are critical focus areas in the (bio)pharmaceutical and medical device industries. Robust cleaning and disinfection programs are required to prevent adulteration, cross-contamination, and microbial contamination of products. Consequently, the selection and number of disinfecting agents used, the frequency of application, and the rotation of (one or more) disinfectants along with a sporicidal agent should be scientifically justified by a formal microbial risk analysis (MRA). The MRA and the chosen cleaning and disinfection program should be supported by periodic review of relevant environmental monitoring (EM) data, and regular auditing of the cleaning and disinfection programs.
Inadequate cleaning and disinfection programs cause significant risk to patient safety, financial loss to the company and product recalls1-5. Recurring microbial contamination generally results from inadequate cleaning and disinfection procedures associated with an ineffective root-cause investigation. Control of microbiological contamination and root-cause investigation (see CFR211.113 a and b, and CFR211.192) are among the top 10 most observed deficiencies by the FDA since 20126. The situation in Europe is not any different based on recent UK MHRA (Medicines Healthcare products Regulation Agency) deficiencies observed, and the non-compliance reports handed out by European Inspectors7-9.
The objective of the article is first to present the different regulatory requirements and guidance regarding disinfectant rotation. Secondly, the article seeks to answer the question "Is the rotation of more than one disinfectant along with a sporicidal agent mandatory for cGMP compliance?". To be able to fully answer the question, the process of establishing the number of disinfectants (one or more) will be discussed. Finally, the article reaffirms the importance of periodically reviewing microbial data and auditing practices to confirm the effectiveness of the cleaning and disinfection programme including the disinfectant rotation and frequency choice.
8/9 June 2021
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Regulatory Requirements and Guidance on Disinfectant Rotation
The regulatory recommendations regarding rotation of disinfectants are the following:
1. Japan (JP) Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing (2006):
a. "The program should contain procedures for screening and classifying bacterial isolates in each manufacturing environment."
b. "Cleaning agents and disinfectants should be validated for their appropriateness and reliability in removing contaminants prior to use. Cleaning and disinfection efficacy should be assessed and confirmed based on type and count of microorganisms characterized by periodic environmental monitoring."
c. "If selected disinfectants might have inferior efficacy against microorganisms isolated from the environment, the efficacy should be reevaluated and the replacement with or alternate use of different disinfectants should be considered and implemented, as appropriate."
d. "If environmental monitoring data indicate or suggest the presence of spore-forming bacteria or fungi, suitable sporicides or fungicides should be selected for disinfection."
2. United States Food and Drug Administration (US FDA) guidance on aseptic manufacturing (2004):
a. "…. Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility.…."
b. "…Therefore, a sound disinfectant programme also includes a sporicidal agent, used according to a written schedule and when environmental data suggest the presence of sporeforming organisms."
c. "…. If indicated, microorganisms associated with adverse trends can be investigated as to their sensitivity to the disinfectants employed in the cleanroom in which the organisms were isolated."
3. Brazil National Health Surveillance Agency (ANVISA) resolution - RDC n.17 (2010):
a. "Article 315. The sanitation of clean areas is particularly important in the manufacture of sterile products. §1 These areas should be cleaned and sanitized frequently, according to a specific programme approved by Quality Assurance. §2 The areas should be monitored regularly to detect the emergence of resistant microorganisms."
4. European Medicines Agency (EMA) EudraLex Annex 1 (2008):
a. "61. The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains. "
The Pharmaceutical Inspection Convention/ Pharmaceutical Inspection Co-Operation Scheme (PIC/S) - PE 009-13 Annexes (2017) requirements regarding disinfectant rotation are similar to the EudraLex Annex 1 (2008).
Note that based on these excerpts, the reader might be confused about the rotation definition. Is it one disinfectant alternated with the use of a second disinfectant? Or, is it one or more than one disinfectant with a sporicidal agent? Several articles defining rotation have already been published10-13.
Different nongovernmental organizations have published recommendations on cleaning and disinfection programs design and disinfectant rotation14- 16. The rotation definition should be adequately defined in the cleaning and disinfection procedures.
General chapter from the pharmacopeias or technical documents from nongovernmental organizations are not mandatory requirements. However, this information might include some recommendations that should help firms to meet cGMPs:
1. United States Pharmacopeia (USP) <1072>:
a. "The rotation of an effective disinfectant with a sporicide is encouraged. It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent."
b. "Other disinfection rotation schemes may be supported on the basis of a review of the historical environmental monitoring data."
c. "…the most frequently isolated microorganisms from an environmental monitoring programme may be periodically subjected to use-dilution testing with the agents used in the disinfection programme to confirm their susceptibility, as there are real differences among different species in resistance to the lethal effects of different sanitizers."
2. Parenteral Drug Association (PDA) Technical Report (TR) 70:
a. "Today, most firms use a system whereby a disinfectant is rotated with a sporicide to more effectively reduce the bioburden levels."
b. "All rotation systems should be evaluated via the use of area classification, environmental monitoring data, and/or risk assessment."
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Live Online Training: Risk Assessment in Contamination Control
The regulatory guidelines agree on the idea that a routine disinfectant must be active against vegetative microbial flora recovered from the facility or isolates. The effectiveness of the disinfectants and the sporicides must be demonstrated through a disinfectant validation (laboratory testing such as suspension and coupon testing and in-situ testing) and confirmed through environmental monitoring and data trending over time. Finally, the EM programme should be designed to detect most frequent isolate microorganisms and worst-case microorganisms (e.g. spores or fungi) or "resistant" strains/microorganisms. The terminology used by the USP "most frequent isolate" is considered as more accurate for (bio) pharmaceutical and medical device firms than the term "resistant microorganism." It is expected that where EM data shows the presence of spore-forming organisms, that sporicidal agent will be used. Note that this last statement is not specified in the EU GMP Annex 1 revised in 2008. Finally, the draft EU GMP Annex 1 requires that a cleaning and disinfection programme should include periodic use of a sporicidal agent.
Finally, the regulatory guidelines are not aligned regarding the number of disinfectants required in conjunction with a sporicidal agent (disinfectant rotation). However, the USA FDA, JP and ANVISA guidelines expect the manufacturer to justify the number of disinfectants and the rotation based on EM data review. However, the EU GMP requires the use of at least more than one type of disinfectant, where a disinfectant is used15, 17. In addition, the draft Annex 1 available for public consultation proposes that "More than one type of disinfecting agent should be employed, and should include the periodic use of a sporicidal agent." Isn't this paradoxical with the quality risk management principle promoted in the different recent EU guidelines revisions? The cleaning and disinfection programme should be considered as part of the EM programme lifecycle approach. Consequently, the number of disinfectants used along with a sporicidal agent should be justified by a formal MRA, periodic EM data review and periodic auditing of the cleaning and disinfection procedures rather than being arbitrarily imposed.
In the next issue of the GMP Journal you will find out about the lifecycle approach for confirming the disinfection rotation programme.
Walid El Azab
... is a Technical Services Manager for STERIS Life Science. He currently provides technical support related to cleaning chemistries, disinfectants and sterility assurance products and their application and validation. Walid is an Industrial Pharmacist and is Secretary of the Belgium Qualified Person association.
1 Macher, J. Business Case for Quality. Pharmaceutical Quality Systems (ICH Q10) Conference. (2011)
2 Sutton, S and L Jimenez., A Review of Reported Recalls Involving Microbiological Control 2004-2011 with Emphasis on FDA Considerations of "Objectionable Organisms", American Pharmaceutical Review, 15, 42-57, (2012).
3 Hayes, R.J. Cost of Quality (CoQ) - An Analysis of the Cost of Maintaining a State of Compliance. (2014) Int. Pharm. Ind. 6(1), 74-76.
4 Cundell, T. Mold Monitoring and Control in Pharmaceutical Manufacturing Areas. (2016) Am. Pharm. Rev., 19(5).
5 $18.2 million in settlement over mold at manufacturing facility, access on Jul 1, 2017 at: http://www.modernhealthcare.com/article/20170112/NEWS/170119945.
6 United States Food and Drug Administration (US FDA), Summary of Inspectional Observations by Fiscal Year, access on May 25, 2017 at: https://www.fda.gov/ICECI/Inspections/ucm250720.htm.
7 Medicines & Healthcare products Regulatory, MHRA GMP Inspection Deficiency Data Trend 2015, access on May 25, 2017 at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/582841/MHRA_GMP_Inspection_Deficiency_Data_Trending_2015.pdf.
8 Medicines & Healthcare products Regulatory, MHRA GMP Inspection Deficiency Data Trend 2016, access on May 25, 2017 at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/609030/MHRA_GMP_Inspection_Deficiency_Data_Trend_2016.pdf 9 EudraGMDP Non-compliance Report observed by the European Inspectors from February 2015 to May 2017, access on Jul 1, 2017 at: http://eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do
10 Smith, J. "Rotational Cleaning-Is It Necessary?" Cleanroom Technology (January 2014)
11 Martinez, JE "The Rotation of Disinfectant Principle True or False?" Pharmaceutical Technology (2009)
12 Sutton, S. "Disinfectant Rotation in a Cleaning= Disinfection Program for Clean Rooms and Controlled Environments" CRC Press Taylor Francis (2007), issued by Gurusamy Manivannan
13 Sutton, S. "Disinfectant Rotation a Microbiologists View" Cleanrooms, 2005, access on May 25, 2017 at: https://www.cemag.us/article/ 2005/07/disinfectant-rotation-microbiologists-view
14 PDA Technical Report Number 70: Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing Facilities (2015)
15 European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 1, Manufacture of Sterile Medicinal Products.
16 United States Pharmacopeia 38 (USP) <1072> - Disinfectants and Antiseptics. The United States Pharmacopeia Convention/National Formulary, Rockville, MD.
17 Sandle T., a guide to cleaning and disinfecting cleanrooms, 3. Ausgabe, the CDC Handbook, 2012, S. 173-180.