In a previously published article entitled “The pain of change”, I postulated that because of the level of regulation of drugs and drug products or devices in place to ensure patient safety, the Life Sciences industry can often seem conservative, slow to react, and unwilling to move away from historic procedures and practices. I also went on to recognize that counterintuitively, a constant feature for what can appear to be a conservative industry, is change, with manufacturers required to have a process of continuous improvement.
Other commentators have more daringly asked the question “Which is more important to you: complying with industry and federal regulations or improving the efficiency and profitability of your operations?”2 At the same time they have reminded us that in highly regulated industries (pharmaceutical, medical device, nuclear, natural resource extraction, and aerospace to name a few) the “…. cost of noncompliance is often higher than the opportunity cost of incremental improvements to processes”.2
The very nature of creating and maintaining a robust QMS can result in processes becoming rigid. This can lead to change – even necessary or desirable change ‐ being avoided, knowing it could attract scrutiny and therefore, would have to be carefully explained during a regulatory audit. Add to this a fast‐paced industry that is typically ‘lean’ and therefore time and labor-challenged, and change can often be seen as something that is best left until tomorrow.
This mindset of efficiency improvements conflicting with the perceived risk of compliance change was supported by a study by McDermott et al. in Barriers and Enablers for Continuous Improvement Methodologies within the Irish Pharmaceutical Industry. It found that 45% of the study participants perceived that a highly regulated environment could be a barrier to continuous improvement implementation. However, 97% of respondents utilized Continuous Improvement (CI) methods within their organizations. It went on to state that the highest motivation for CI implementation amongst the Irish Pharma industry was to improve Productivity and Quality, with the main obstacles for CI implementation within stringent regulatory regimes being fear of extra validation activity, a compliance versus quality culture, and a regulatory culture of being “safe”.1
As a reminder, EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Chapter 1 Pharmaceutical Quality System states:
“1.4 A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that: (i) Product realization is achieved by designing, planning, implementing, maintaining, and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes.”
ICH guideline Q9 on quality risk management (EMA/CHMP/ICH/24235/2006) Annex II.1 Quality risk management as part of integrated quality management, also identifies potential uses of quality risk management principles and tools by industry and regulators. It also includes continual improvement used to facilitate improvement in processes throughout the product lifecycle.
It is clear then that the need for continuous improvement is embedded into the requirements of GMP to reduce risk, ensure optimum product quality, and reduce the potential for non‐compliance. However, it is also recognized that change and improvement can equally lead to significantly beneficial outcomes in aligning and harmonizing procedures and processes across multiple sites within the same organization, and help to move us towards more sustainable, safe, and efficient ways of working.
Anyone currently working within the pharmaceutical industry or who has done so in the last 30 years will be familiar with or at least be aware of a wide range of continuous improvement methodologies or tools in use, such as Lean, kaizen, Six Sigma, 5s, agile or even a mix of all of these and perhaps others.
What each of these methods has in common is that they help organizations that use them to identify areas of inefficiency to then implement appropriate solutions, in what have been described as “…. ever-tightening cycles of improvement. These cycles are ongoing— continuous. There is no horizon to continuous improvement, just gradual, cumulative progress”.2
So what are the specific areas related to cleaning, disinfection, and automated bio‐decontamination of controlled manufacturing areas that can be positively impacted by a continuous improvement mindset?
As stated previously, the need for continuous improvement is embedded into the requirements of GMP so it is here that we should start, with quality and compliance.
Quality and Compliance
All elements of any cleaning and disinfection regime should be subject to periodic scrutiny to ensure that they are still fit for purpose and are in line with best practice and regulatory expectations.
Arguably, these regimes which are often historic to a site and in some instances with little documented rationale as to how they were developed or decided upon, can often be an area where there is substantial resistance to either change or adapt them.
To give examples, EudraLex Vol 4. Annex 1 Manufacture of Sterile Medicinal Products (2022) section 4.35 discusses the acceptance of certification from detergent and disinfectant suppliers, and strongly intimates that there is a need for “successful completion of…. appropriate vendor qualification.” Section 4.33 advises end users that “More than one type of disinfecting agent should be employed ... Disinfection should include the periodic use of a sporicidal agent.”
Section 4.34 informs us that “The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used.”
More recent clarifications to the Annex have resulted in the wording in section 4.33 that “Cleaning programs should effectively remove disinfectant residues.”
So we can see that it is a requirement to use pre‐approved, reputable suppliers of detergents and disinfectants, select more than one disinfection agent and have a regime that includes periodic (proactive rather than reactive) sporicide use, and ensure that these disinfectants are suitably validated. It is also made clear that any residues left on surfaces from detergents and/or disinfectants must be managed, which may involve the introduction of inefficient rinsing steps.
Failure to critically examine the chemistries in use on a site and introduce changes and improvements where they are identified and required to address these specific areas may result in risk to quality and compliance. These risks can be through the use of inappropriate materials where the quality or consistency may vary, the introduction of, and failure to, manage chemical and particulate contaminants on site (residues), or failure to ensure that the regime and rotation in use are suitable to maintain the appropriate level of control (validation).
Operational Efficiency
Once again, cleaning and disinfection regimes that are historic, and may not have a robust, documented rationale as to how they were developed or decided upon may be blindly followed for years without being objectively examined to ensure they are still fit for purpose. This is particularly true where there may not have been any significant observed issues with efficacy or microbial excursions. However, the increased focus on residues and the continued attention to the safety of operators handling these chemicals and performing these tasks means that the amount of time and labor being allocated to cleaning and disinfection activities is being increasingly scrutinized.
The efficiency of cleaning and disinfection regimes can be impacted by disinfectants that may require multiple applications to achieve impractically long contact times, detergents or disinfectants that may need complicated preparation (and validation and ongoing documentation of this activity) or labor and water-intensive additional rinsing steps to manage or reduce residues. Given that many of these tasks are typically performed multiple times per day in most facilities, the potential for inefficiency is evident.
Many organizations procure or provide formal training for their employees in Operational Excellence (OPEX), to both initiate and support the continued drive for sustainable profitability and growth within the organization and to build continuous or process improvement capabilities. However, how often these OPEX programs detail cleaning, disinfection, and bio‐decontamination is unclear. When these practices are overlooked, significant efficiency gains may be missed.
Global Harmonization
For several decades, mergers and acquisitions (M&A) have played a significant role in most pharmaceutical companies’ growth strategies. These repeated processes have seen large companies consolidating, and other small to medium size or emerging companies (particularly biotechnology or biopharma companies) being acquired by larger players.
The result of this M&A process can be pharmaceutical manufacturing companies that have multiple sites, producing multiple products and types and formats of medicines, with the consequence that a single organization may be using a wide range of detergent and disinfectant vendors and have cleaning and disinfection processes that vary significantly over different manufacturing sites.
Disinfectants used in controlled manufacturing environments should be sourced from reputable suppliers that have undergone vendor qualification and have validation that is representative of the facility they are used in, in the way they are used, and be applied using consistent, reproducible, best practice application techniques.5-7
For companies with multiple sites, trying to ensure regulatory compliance, this can result in a repetition of selection, validation training, and implementation processes for each manufacturing location or facility, with all the associated cost and resource constraints. Alternatively, if legacy regimes are left in place at each site, and no effort is made to look at the benefits of harmonization, then differences in cleaning and disinfection regimes and practices invariably persist or develop over time.
Failure to address these disparate practices may result in unintended consequences, including less control over vendors and materials in use, sub‐optimal or complex regimes, and differences in rotation frequencies and application techniques which can be difficult to reconcile when scrutinized during inspection or audit.
Sustainability
There is currently a broad scientific consensus on climate change, with 97 percent agreement among climate scientists that humans are causing global warming.8
The signs of climate change are already happening, and governments and corporations are starting to react, with additional efforts being made. In Europe, the EU has committed to ambitious, long-term environmental and climate goals that will inevitably drive a change in the way we currently manufacture.4
We have already seen some significant commitments by leading pharmaceutical manufacturers around waste disposal, water consumption, reduction in greenhouse gas emissions, total carbon footprint neutrality, and plastic neutrality for their manufacturing operations and wider organizations.
There is also industry commitment around water scarcity and creating a ‘circular economy’, with many CEOs keen to ensure that environmental protection and sustainability targets are cascaded down from the boardroom through the wider business. To do this, all elements of cleanroom manufacture need to be looked at, from energy-intensive use of HVAC systems and water purification, right down to specific activities such as cleaning and disinfection.
Objectively looking at current products in use, and where needed, making sure that the selection, validation, and implementation of detergents and disinfectants consider sustainability, and favor those that have less impact on the environment in their production, packaging, or presence in effluent discharge, is increasingly occurring.
Using products that require less rinsing can also have a significant impact on the amount of water used, and the amount of rinse water containing cleaning and disinfection chemicals being sent to drain over a typical year of manufacturing. Implementing highly effective automated bio‐decontamination technologies that use a fraction of the chemicals or water compared to manual disinfection can also be a major step in reducing the energy and waste footprint.
In making a change, and to support their sustainability targets, pharmaceutical companies should ensure the implementation of cleaning and disinfection products is from reputable, market-leading vendors who have either already lessened the impact of chemical production, packaging, and transportation; or who have a robust roadmap in place to do so.
Safety
It should go without saying that one of the greatest assets of any company is its workforce. Employers have a duty of care to look after and protect the health and safety of their employees, from a legal, financial, and moral perspective.
Legacy cleaning and disinfection regimes can expose a company to challenges around health and safety when active chemicals are reclassified, or when changes to occupational exposure limits (OELs) or Personal Protective Equipment (PPE) requirements are introduced.
Examples have been seen where end users have embarked on a change to cleaning and disinfection chemistries as a reaction to slips, trips, or falls caused by residues left behind on floors. Chemicals that have caused adverse (material or chemical) reactions, consequently damaging surfaces or expensive equipment and posing challenges to the safety and integrity of the cleanroom environment can also require a critical re‐examination of the types of materials being used for cleaning and disinfection.
These factors can in turn make it more important to ensure that vendors supplying them are ahead of legislation that may impact how products can and should be used, with reputable suppliersproactivelyy monitoring and engaging with BPR, ECHA, and other relevant legislation.
Cost Savings
Unless they are significant, cost savings on their own are not usually a reason to undertake changes to cleanroom cleaning and disinfection regimes and practices.
As highlighted by McDermott et al. one of the highest motivations for continuous improvement implementation is to improve Productivity and Quality, with the main obstacles being fear of extra validation activity, compliance, and moving from well-known, comfortable practices that may be considered “safe”.1
Any changes to a company’s practices will quite correctly be scrutinized during regulatory or customer audits or inspections to ensure that quality is never being sacrificed in the drive towards simply reducing cost, lean operation, and efficiency.
However, the need to continuously balance quality and compliance, operational efficiency, global harmonization, sustainability, safety, and cost savings can all exert differing pressures at any one time on processes and practices in place and may require change to be implemented.
Considering the impact of selected chemistries on water usage, whether it be for dilution of concentrates or water required for rinsing off and management of detergent and disinfectant residues (see previous sections) is one obvious improvement or saving. However, other less tangible or quantifiable savings of critically examining, and where required adapting or changing regimes may include increased compliance, leading to fewer regulatory observations, simpler procedures, and leaner vendor and inventory management.
Selecting vendors of cleanroom detergents and disinfectants that can provide added value support services to support changes to cleaning and disinfection regimes and practices can also help reduce the burden, and cost of change.
Change Management
As we have seen, there are many reasons why changes may be needed to any cleaning, disinfection, and bio‐decontamination practices. The objective is for manufacturers in regulated industries to have continuous, improvement. Whilst the lack of internal resources can often obstruct the implementation of change, be it a full regime overhaul or the introduction of a single new product, extensive or minor change, this improvement process must be always ongoing to ensure that processes are continuously reviewed and optimized.
Forward‐thinking process changes in pharmaceutical, biotechnology, or medical device manufacturing environments are critical, and practical support with change can help to ease the burden of continuous improvement and ensure change is seen as a positive as well as necessary process.
As the pharmaceutical industry would look to other vendors to provide expertise and undertake some of the tasks required to introduce new equipment (such as IQ, OQ, PQ), in the same way, suppliers of cleaning and disinfection products should have the expertise and programs to ease the acceptance, approval, and implementation of change enabling you to focus on the core of your pharmaceutical business.
References
- McDermott, O.; Antony, J.; Sony, M.; Daly, S. “Barriers and Enablers for Continuous Improvement Methodologies within the Irish Pharmaceutical Industry.” Processes 2022, 10, 73. https:// doi.org/10.3390/pr10010073
- Rony Kubat, Balancing Compliance and Continuous Improvement in Highly Regulated Industries | 2019‐10‐08 | Quality Magazine.
- Cleanroom Technology, “The pain of change: Could disinfectant suppliers be part of the cure?” 29 March 2023. https://www.cleanroomtechnology.com/news/article_page/ The_pain_of_change_Could_disinfectan t_suppliers_be_part_of_the_cure/207870)
- European Environment Agency statement on Sustainability. Modified 19 Dec 2023,
- https://www.eea.europa.eu/en/topics/at-a-glance/sustainability
- FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice Aseptic Processing (2004): “3. Disinfection Efficacy. The suitability, efficacy, and limitations of disinfecting agents and procedures should be assessed. The effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces…. Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility.”
- PIC/S PI 007‐6 Validation of Aseptic Processes (2011): “9.4.3 The effectiveness of disinfectants and the minimum contact time on different surfaces should be validated.”
- EudraLex Vol. 4, Annex 1: “4.34 The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used.”
- Earth Science Communications Team, NASA’s Jet Propulsion Laboratory | California Institute of Technology. January 30, 2024 (Do scientists agree on climate change? – Climate Change: Vital Signs of the Planet (nasa.gov))
Author Details
Matt Cokely, Global Technical Consultant Strategic Director - ECOLAB
With over 10 years working within the pharmaceutical industry as a Pharmaceutical Microbiologist, Matt Cokely then joined Ecolab, and since then has continuously worked with pharmaceutical customers for over 15 years advising on regulatory and technical aspects of cleaning and disinfection of controlled areas and graded cleanrooms.
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 4 Mayy/June 2024Pages: 48-52
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