Cell-based therapies call for better performing equipment

Recently, the success of cell and immune-mediated therapies has enhanced the possibilities for cell-based therapies as a mainstream form of treatment across the globe.1

As stem cell research and regenerative medicine grow and gain clinical importance, fundamental laboratory equipment that is reproducible, reliable and can deliver contamination-free performance is vital to the quality process.

Laboratories and other environments working with biologically relevant products typically need a controlled, clean environment to ensure sample integrity is preserved. Contamination events can be a burden on both time and resources, leading to considerable delays in research, as well as impeding patients’ ability to receive therapeutic treatments.2

One of the most effective precautions laboratories and clinical manufacturers can take to prevent contamination is making sure cleanrooms meet Good Manufacturing Practice (GMP) guidelines. GMP regulations are applicable to each stage of cell collection, processing and storage.3

Threats to cell culture-based product production

Sterile or aseptic assurance is a key operating condition when manufacturing living cell/tissue products that cannot be easily sterilized. Inherently, initial cell and biological materials are susceptible to contamination from microorganisms and viral contaminants.4

Given that microparticles in atmospheric air have a potentially infectious nature, ensuring the cleanroom environment meets guidelines with appropriate equipment significantly reduces the risk of potential stressors and exposure to contaminants.5

Other mammalian cells may be the origin point of cell culture contaminants as well as microbial sources or even a non-living source. No matter what form or origin these contaminants take, their presence in cell cultures can adversely impact results, producing genetic instability, transformation, alterations in normal physiological function and changes in viral susceptibility.6

A number of contaminants can be identified in the early stages of culturing using visual cues, while other contaminants are more evasive and difficult to identify. For instance, it is relatively easy to detect microbe and mycoplasma, while contamination from viruses is more complex.

In fact, viral contamination does not typically present in overall morphological changes; rather, it is expressed in DNA changes that cannot be easily discerned from visual inspection.7 Viral infection may have its origins in contaminated cell lines, contaminated raw materials, or a GMP breakdown in the production and purification process.8

Primary contamination also means that there is an increased risk of cross-contamination to other products, which may lead to an even greater loss of resources and time.

What is a cleanroom classification?

A cleanroom environment is where the concentration of airborne particles like dust, microbes and aerosol particles is carefully controlled. Cleanrooms are maintained and utilized in a manner that significantly reduces or eradicates the introduction, generation and retention of particles in the surrounding environment.

All cleanrooms that comply with GMPs standards are classified according to the cleanliness level of the air inside.9 Meeting requirements for cleanrooms is one of the key issues for laboratories when adhering to GMP requirements.

The International Organization for Standardization (ISO) is a nongovernmental body tasked with the promotion of global standards to ensure safe, reliable, and high-quality products. It developed classifications affiliated with the levels of cleanroom certification.

ISO awards cleanroom designations predicated on a threshold of particles permitted within a specific area (Table 1). According to GMPs requirements, cleanroom classifications should meet ISO 14644-1. This ISO classification has an influence on every cleanroom user in the GMP community.

Table 1. Cleanroom Classes as defined in GMP. Source: PHC Europe B.V.

FED209 Approximate
Cleanroom Equivalent Class
GMP Approximate
Class Equivalent Class*
ISO Designation ≥ 0.1 μm ≥ 0.2 particles/m3 ≥ 0.3 particles/m3 ≥ 0.5 particles/m3
100 Grade A/B 5 100,000 23,700 10,200 3,520
1000   5.5 316,000 74,800 32,200 11,100
1000   6 1,000,000 237,000 102,000 35,200
10,000   6.5 3,160,000 748,000 322,000 111,100
10,000 Grade C 7       352,000
100,000   7.5       1,110,000
100,000 Grade D 8       3,250,000

ISO decimal classes, including ISO Class 5.5, are designated at intermediate thresholds according to ISO 14644-1, Annex E, which states, “specification of intermediate decimal cleanliness classes and particle size thresholds.”
* Equivalent GMP Grades as defined by the World Health Organization (WHO).

Who needs an ISO-Certified cleanroom?

There are a number of laboratories and clinical facilities that require a good cleanroom for various reasons. Contaminants or particles in the air have a significant impact on the process of both testing and manufacturing samples and products.

The creation of particles by certain laboratory equipment can mean degradation occurs at accelerated rates, which may result in a total loss of biologically relevant material.10

Seven of the top ten best-selling drugs of 2019 were biologics (Table 2).11 When producing biological products, it is crucial to take into account that any variances during the manufacturing process, irrespective of how small, may have a significant impact on product quality and efficacy.12

Table 2. Drug Type and Route of Administration of the Top Drugs of 2019. Source: PHC Europe B.V.

    Humira Keytruda Revlimid Imbruvica Opdivo Eliquis Eylea Enbrel Avastin Rituxan
Biologic Intravenous   Cell-based therapies call for better performing equipment     Cell-based therapies call for better performing equipment       Cell-based therapies call for better performing equipment Cell-based therapies call for better performing equipment
Subcutaneous Cell-based therapies call for better performing equipment             Cell-based therapies call for better performing equipment   Cell-based therapies call for better performing equipment
Intravitreal             Cell-based therapies call for better performing equipment      
Small Molecule Oral     Cell-based therapies call for better performing equipment Cell-based therapies call for better performing equipment   Cell-based therapies call for better performing equipment        

 

Therefore, within GMP facilities, it is vital that clean areas are classified accurately. One of the early steps in this process is ensuring furniture and equipment are cleanroom certified. GMP compliance can be followed when consistent GMP-grade materials from well-characterized sources are installed and used.

Cell-based therapies call for better performing equipment

Image Credit: PHC Europe B.V.

Cleanroom classified equipment

It is important to maintain appropriate attire/gowning, furniture and equipment to reduce the risk of particles and contaminants entering cleanroom environments. Equipment that is not certified for cleanroom settings can represent a variety of obstacles when it comes to appropriate cleanroom maintenance.

For instance, uncertified tools and equipment with motors and other moving parts can release a significant amount of particles into the environment. Some tools and equipment considered essential are also equipped with engines and other devices that have a whole host of potential particles to shed.

According to ISO 14644-1 and in relation to airborne particle cleanliness, “Part 14: Assessment of suitability for use of equipment by airborne particle concentration” was developed to evaluate the suitability of equipment for use in cleanrooms.

This section of ISO 14644-1 details the methods required to determine the total particle emission of equipment and offers data that may be applied to establish the particle load in a cleanroom.

For all equipment classified by an internationally recognized safety certification company, testing must be compliant with the methodology of particle emission as stated in part 14 of ISO 14644-1.

Additionally, prior to testing, the certification company must make sure all equipment complies with the design principles of a cleanroom as described in part 14 of ISO 14644-1.

As ISO guidelines state, these principles ensure that equipment is manufactured with suitable materials and surface finishes, prevention of static air zones, design principles of cleanability and considerations for maintenance.

To ensure that PHC’s equipment is trustworthy when being used as an essential tool for cleanroom applications, the company has invested in the classification of its flagship cold storage and cell culture incubators. Equipment that is compliant with GMP standards is ISO cleanroom classified by an independent approved testing laboratory.

PHC is fully aware of the fact that ISO classified cleanroom equipment is crucial when ensuring high quality, repeatable results that meet cleanroom and GMP standards are maintained. PHCbi products have been carefully developed,  designed, engineered and fabricated to fit smoothly into any space or protocol.

Engineered with cell health as the central focus, PHCbi MCO incubators have a minimum amount of moving parts and complement decontamination protocols while significantly reducing contamination risks.

PHC’s ultra-low temperature freezers are constructed with a unique sealed refrigeration system, paired with a sealed bearing design on the cooling fans to limit particle emissions.

While the preservation of laboratory quality standards has always been important, the increased focus on strictly controlling environments will continue to expand with stem cell research and regenerative medicine demands.

Therefore, as cleanroom classification for GMP manufacturing becomes increasingly important, it is essential to closely evaluate core laboratory equipment and its role in enabling a suitable cleanroom status.

Cell-based therapies call for better performing equipment

Image Credit: PHC Europe B.V.

Testing methodology

Each unit has received the requisite classification following the testing methodology listed below:  

  1. Testing was conducted in a dynamic environmental chamber with predetermined air, temperature and humidity conditions.
  2. The cleanliness of the chamber is quantified in accordance with ISO 14644-14:2016.
  3. 24 hours before testing, the device is loaded into the chamber and equilibrated.
  4. Particle count concentrations are then monitored for 120 minutes. Particle concentrations (number of particles/m³) were measured for particles in size ranges of ≥ 0.1 μm, ≥ 0.2 μm, ≥ 0.3 μm and ≥ 0.5 μm in diameter.
  5. The average particle concentrations, upper confidence limit in the empty chamber and relative ISO Class ratings are calculated and defined in line with ISO 14644-1:2015.

PHC Europe can supply a complete product line that is representative of over 50 years of experience, successful application and innovation throughout the life science community. If clients are looking to develop GMP manufacturing, PHC can help.

To discover more, contact a PHCbi brand representative at www.phchd.com/eu/biomedical.

Cell-based therapies call for better performing equipment

Image Credit: PHC Europe B.V.

References

  1. Balendu Shekhar Jha, Mitra Farnoodian, and Kapil Bharti, “Regulatory considerations for developing a phase Iinvestigational new drug application for autologous induced pluripotent stem cells-based therapy product.” Stem Cells Translational Medicine. (August 2020): 10:198–208, https://doi.org/10.1002/ sctm. 20-0242 PMID: 32946199
  2. Barone, P.W., Wiebe, M.E., Leung, J.C. et al. “Viral contamination in biologic manufacture and implications for emerging therapies.” Nature Biotechnology 38, (April 2020): 563–572, https://doi.org/10.1038/s41587-020-0507-2 PMID: 32341561
  3. Ottria G, Dallera M, Aresu O, Manniello MA, Parodi B, Spagnolo AM, and Cristina ML. “Environmental monitoring programme in the cell therapy facility of a research centre: preliminary investigation.” Journal of Preventive Medicine and Hygiene 51, no. 4 (Dec 2010):133-8. PMID: 21553557
  4. Geraghty RJ, Capes-Davis A, Davis JM, et al. “Guidelines for the use of cell lines in biomedical research.” British Journal of Cancer. 111, no. 6 (August 2014): 1021-46, doi:10.1038/bjc.2014.166 PMID: 25117809
  5. Segeritz, Charis-P., and Ludovic Vallier. “Cell Culture: Growing Cells as Model Systems In Vitro.” Basic Science Methods for Clinical Researchers (April 2017): 151–172, doi:10.1016/B978-0-12-803077-6.00009-6
  6. David Pamies, Thomas Hartung. “21st Century Cell Culture for 21st Century Toxicology.” Chemical Research in Toxicology 30, no. 1 (January 2017): 43–52, doi:10.1021/acs.chemrestox.6b00269 PMID: 28092941
  7. Merten, OW. “Virus contaminations of cell cultures – A biotechnological view.” Cytotechnology 39, (June 2002): 91–116, doi.org/10.1023/A:1022969101804 PMID: 19003296
  8. Bae, J.E., Kim, I.S. “Multiplex PCR for rapid detection of minute virus of mice, bovine parvovirus, and bovine herpesvirus during the manufacture of cell culture-derived biopharmaceuticals.” Biotechnology and Bioprocess Engineering 15, (February 2011): 1031–1037, doi.org/10.1007/s12257-009- 3137-6
  9. “Current Good Manufacturing Practice (CGMP) Regulations.” U.S. Food & Drug Administration (FDA), last modified 09/21/2020. www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practicecgmp-regulations  
  10. Fernando Cobo, David Grela, and Ángel Concha. “Airborne particle monitoring in clean room environments for stem cell cultures.” Biotechnology Journal, 3, no. 1 (January 2008): 43-52. doi.org/10.1002/biot.200700122 PMID: 18034434
  11. Yip, Stephanie. 2021. Pharmaintelligence.Informa.Com. https://pharmaintelligence.informa.com/~/media/informa-shop-window/pharma/2020/files/reports/top-10-best-selling-drugs-of-2019.pdf  
  12. Moutsatsou, P., Ochs, J., Schmitt, R.H. et al. “Automation in cell and gene therapy manufacturing: from past to future.” Biotechnology Letters, 41 (September 2019): 1245–1253 doi.org/10.1007/s10529-019-02732-z PMID: 31541330

About PHCi

Founded in 1990 as subsidiary of the PHC Holdings Corporation, it is our mission to become a leading, trusted brand for sustainable healthcare and biomedical product solutions, which support the work of our customers to improve the health and well-being of people around the world.

For more than 25 years now, we respond to the needs of our pharmaceutical, biotechnology, hospital/clinical and industrial customers, offering an unique perspective on scientific research in general. As a result we play a critical role in product development for worldwide applications and have established a reputation as a manufacturer of high-quality and innovative medical and laboratory equipment.

Long lasting relationships have been built with leading pharmaceutical, healthcare and biotechnology companies as well as with major academic and research institutes in Europe. PHC Europe B.V. has set the standard in many aspects. V.I.P. panels, Cool Safe compressors, Active Background Contamination Control and the world’s first -152°C ULT freezer. Where PHC Europe B.V. took the initiative, the others followed. This made us a very important player in both the ultra-low temperature and the CO2 market.


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Last updated: Jun 9, 2022 at 10:07 AM

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