The quality attributes of manufactured pharmaceutical products include the physical, chemical, and microbiological characteristics of the raw materials, excipients and active pharmaceutical ingredient (API), as well as the final drug product (see Table 1). Absence of microbiological contamination is considered a critical quality attribute due to its potential to dramatically impact, directly or indirectly, the safety and/or the efficacy of the drug product.
A large proportion of products labelled as sterile are manufactured by aseptic processing rather than terminal sterilisation. Because aseptic processing relies on the exclusion of microorganisms from the process stream and preventing microorganisms from entering open containers during processing, product bioburden – as well as the bioburden of the manufacturing environment – are important factors governing the risk of unacceptable microbial contamination. The terms ‘aseptic’ and ‘sterile’ are not synonymous. ‘Sterile’ is derived from the Latin sterilis (unfruitful), meaning, in modern terms, free from living germs or viable microorganisms that have the potential to reproduce. In contemporary aseptic healthcare product manufacturing, ‘aseptic’ describes the process for handling sterilised materials in a controlled environment designed to maintain microbial contamination at levels known to present minimal risk.1 Therefore, the importance of adequate and effective microbiological controls cannot be overstated.2
This report addresses the key factors shaping pharmaceutical formulation, including regulation, QC and analysis.
Access the full report now to discover the techniques, tools and innovations that are transforming pharmaceutical formulation, and learn how to position your organisation for long-term success.
What you’ll discover:
Key trends shaping the pharmaceutical formulation sector
Innovations leading progress in pharmaceutical formulation and how senior professionals can harness their benefits
Considerations and best practices when utilising QbD during formulation of oral solid dosage forms
Can’t attend live? No worries – register to receive the recording post-event.
Control of the environment in which pharmaceutical products are manufactured is a key element of Good Manufacturing Practice (GMP). Included in this control, the monitoring of microbial contamination is essential.3 Physical and microbial monitoring of manufacturing cleanrooms, restricted-access barrier systems (RABS), and isolators should include the components listed in Table 2, which summarises the major components of an environmental monitoring (EM) programme. Evaluating the quality of air, surfaces, personnel garments and behaviours in a cleanroom environment should start with a well-defined written programme, employing scientifically sound methods of sampling, testing, and data analysis.4
Compressed gases: a brief regulatory overview
As shown in Table 2, the testing and monitoring of compressed air and other process gases, such as gaseous and liquid nitrogen, oxygen, argon, and carbon dioxide, that come into direct contact with pharmaceutical drugs during the manufacturing process is vital to assuring the quality and safety of these products. Compressed air is a critical process parameter, whose variability has an impact on the critical quality attribute (see Table 1) and should therefore be monitored or controlled to ensure the process produces the desired quality.
Unlike the food industry, the pharmaceutical industry does not have a clear-cut guideline or regulation that specifically addresses compressed air quality requirements, testing frequency, or number of samples. The individual manufacturer is responsible for assessing the risk and the effect that a contaminated compressed air supply could have on the final product. The following is a list of three documents from the International Council for Harmonisation (ICH) general guidance on developing a process for the commercial manufacturing of a new pharmaceutical product:
ICH Q8(R2) (Pharmaceutical Development)
ICH Q9 (Quality Risk Management)
ICH Q10 (Pharmaceutical Quality System).5
In addition, some national standards organisations, such as the Compressed Gas Association (CGA) and the National Fire Protection Association (NFPA), provide guidance documents for compressed air sampling. The FDA and EU GMPs also mention that compressed gases should have similar or better physical and microbiological quality than the cleanroom air located in the area where the gases are used. Additional references are the FDA 21 CFR 100. 40 (Avoiding contamination with food additives) and 21 CFR 211. 113 (Control of microbiological contamination).
Table 1: Definitions of quality attributes
Quality attribute
A physical, chemical or microbiological property or characteristic of a material
Key quality attribute (KQA)
Potential to impact product quality or process effectiveness
Associated analytical method
Critical quality attribute (CQA)
Directly or indirectly impacts the safety or efficacy of a drug product
Overall, the general methodology and requirements for compressed gases are described in ISO 8573. First released in 1991 and updated in 2001 and 2010, ISO 8573 is now an international standard relating to the quality of compressed gases and contributing to a particle-free environment in pharmaceutical production facilities, both downstream and upstream. The standard consists of nine separate parts, with Part 1 specifying the quality requirements of the compressed gas, and Parts 2-9 specifying the methods of testing for a range of contaminants. This standard provides a variety of purity classes that can be incorporated into a robust quality assurance plan for this critical utility. ISO 8573 consists of the following parts:
Part 1: Contaminants and purity classes
Part 2: Test methods for aerosol oil content
Part 3: Test methods for measurement of humidity
Part 4: Test methods for solid particle content
Part 5: Test methods for oil vapour and organic solvent content
Part 6: Test methods for gaseous contaminant content
Part 7: Test method for viable microbiological contaminant content
Part 8: Test methods for solid particle content by mass concentration
Part 9: Test methods for liquid water content.
Part 1 outlines the required purity classes based on the concentration of particles (such as dirt, rust, pipe deposits) and level of impurities (compressor lubricant, wear particles, vaporized lubricant) (Table 3). Other tests are described in Parts 2 through 9.
ISO 8573 Part 7 specifies a test method for distinguishing viable, colony-forming, microbiological organisms and related components (eg, yeast, bacteria, endotoxins) from other solid particles that may be present in compressed air. One of a series of standards aimed at harmonising air contamination measurements, ISO 8573 Part 7 provides a means of sampling, incubating and determining the number of microbiological particles. The test method is suitable for determining purity classes in accordance with ISO 8573-1, and is intended to be used in conjunction with ISO 8573-4 when there is a need to identify solid particles that are also viable, colony-forming units.
Table 2: Components of an environmental monitoring programme
Type
Component
Characteristics
Purpose
Physical
Total particulate of room or enclosure air
– Total inert and viable particles
– Active sampling
– Particle counter
– Quality of environment
– Root-cause analysis for source of contamination
Differential pressures, positive pressure from a critical area to adjacent area
– 10-15Pa difference
– Sensor
Prevents entry of contaminant particles from adjacent to critical clean area
– Air changes
– Unidirectional air flow
Sensor
Quality of environment
Temperature and relative humidity
Thermometer, hygrometer sensors
Product quality and personnel comfort
Microbiological
Viable counts of room or enclosure air
Microbial counts by active (impactors and others) and passive (settle plate) air sampling
– Quality of environment
– Root-cause analysis for source of contamination
Viable counts on personnel glove and garment surfaces
– Effective personnel training and hygiene
– Microbial counts by contact plates and swabs
– Contamination risk from operators
– Evaluation of aseptic techniques and practices
Viable counts on manufacturing facilities, equipment and instrument surfaces
Microbial counts by contact plates and swabs
Effectiveness of aseptic techniques, and cleaning and disinfection of area and equipment
Compressed Gases
Total particulates and microbial counts
Sampling of gas by adequate particle counter and microbial gas sampling impactor with decompression adapter
Evaluation of compressed gas quality
– Should be of equal or better quality than air in the critical area into which the gas is introduced
Others
– Any other materials and equipment that might produce a risk of contamination
– Analysis of contamination trends
–
–
The presence of viable microorganisms is verified by exposing an agar nutrient to the compressed air sample. Sampling for qualitative and quantitative assessment is also provided in Part 7. A slit-sampler – a type of impaction air tester – is used, together with the method given in ISO 8573-4. Isokinetic sampling of the air is carried out and reduced until it is within the range of the sampler, as identified by the manufacturer. Pressure is reduced to atmospheric conditions and flow measurements are performed to establish compatibility with the manufacturer’s recommendations, or in accordance with ISO 8573-4. Where the flow is known, the time for the exposure of the agar media to the compressed air sample is recorded. Part 7 does not specify limits for microbial contaminants, with USP <1116> or in-house limits typically used instead.
Microbial impactors with compressed gas kit
Figure 1: Example compressed gas setup
Compressed gas kits allow the microbial samplers to perform microbiological monitoring of compressed gases. Figure 1 shows an example setup. This compressed gas kit uses a special diffusion chamber mounted directly to the sampler inlet, the other end of which is connected directly to the high-pressure gas distribution lines.
The sampling is performed at balanced flow, where the compressed gas flow is equal to the sampling flow. The impactor inlet pressure coincides with the pressure of the compressed gas kit diffusion chamber.
For safety reasons – and to regulate the flow rate of the gas into the diffusion chamber – a pressure regulator is installed in the sampling line between the high-pressure gas source and the inlet to the compressed gas kit. A solenoid valve is connected downstream of the regulator and allows the sampler to synchronise the flow of gas with the start of a sample.
Instrumentation and selection criteria
One question users need to ask themselves is: When do I need to perform the decompression of the compressed gas? Some suppliers prefer decompression prior to sampling, and others promote sampling under compression with a subsequent decompression cycle. Gas for pharmaceutical purposes is decompressed before coming into contact with the product. Therefore, sampling after decompression is closer to the actual usage of the gas. In addition, there is no scientific evidence that a decompression of one order of magnitude down to ambient pressure will harm any microorganisms.6
There is no clear guidance from regulatory agencies on how to select an instrument. However, knowing that the decompression of the gas will have no influence on the viability of microorganisms, pharmaceutical manufacturers must select from a variety of instruments based on specific critical selection criteria:
Size and weight
Points of use
Typically difficult to reach – mobile instruments/handhelds preferred
Ease of use
Software/data management capabilities.
Compressed gases need to be tested directly on-line, especially in critical areas. However, in designing a manufacturing line, monitoring points are not always established close to the point of use. Therefore, the connection points are often hard to reach and associated with a cleanroom setup. ISO 14698 states that sampling devices should be selected according to the area being monitored and take into account the effect of the sampling device on the process or environment being monitored.7
The instrument used for sampling must not contaminate the air that passes inside it, in order to avoid contamination of the cleanroom. A contribution to the particle load of the room is unacceptable, as it may create unpredictable events. Another aspect to be considered concerning the effect on the environment is the ability of the instrument to be properly cleaned and disinfected for cleanroom usage.
Table 3: Solid particulate, water and oil concentration per ISO class
ISO8573-1:2010 Class
Solid Particulate
Water
Oil
Maximum number of particles per m3
Mass concentration mg/m3
Vapour pressure dewpoint
°C
Liquid
g/m3
Total oil
(aerosol liquid and vapour)
0.1-0.5 micron
0.5-1 micron
1-5 micron
mg/m3
0
As specified by the equipment user or supplier and more stringent than Class 1
1
≤ 20,000
≤ 400
≤ 10
–
≤ -70
–
0.01
2
≤ 400,000
≤ 6,000
≤ 100
–
≤ -40
–
0.1
3
–
≤ 90,000
≤ 1,000
–
≤ -20
–
1
4
–
–
≤ 10,000
–
≤ +3
–
5
5
–
–
≤ 100,000
–
≤ +7
–
–
6
–
–
–
≤ 5
≤ +10
–
–
7
–
–
–
5-10
–
≤ 0.5
–
8
–
–
–
–
–
0.5-5
–
9
–
–
–
–
–
5-10
–
X
–
–
–
> 10
–
> 10
> 10
Connecting an instrument to any sampling point in the gas line can become challenging as the accessibility is often very low. The size and weight of instrument will be a major consideration factor. Lifting heavy instruments to a sampling point close to the ceiling or pushing a huge enclosure below a filling line may become a tough exercise. Preferably, instruments should be flexible in usage and easy to carry and lift.
Instrumentation financials and return on investment
Aspects to consider when determining the right investment:
Return on investment: rare measurement vs investment
Multi-functional instruments vs dedicated instrumentation.
Monitoring compressed gases is not a frequent event in a facility’s environmental monitoring programme. Monitoring is typically performed during the first classification of the cleanroom. After the initial test, the test should be run monthly for six months, and if these results are satisfactory, the test should be performed quarterly for the rest of the first year. After the first year – and if the results are still satisfactory – the frequency can be lowered to twice per year in an ISO 5 area, corresponding to each cleanroom verification performed every six months in Europe, but reduced with good justification to once per year in the US.
Testing is not frequent, and investing in dedicated equipment with associated costs like validation, maintenance and repair, is difficult to justify financially. However, it is a mandatory regulatory requirement to monitor gases in facilities, with two optional strategies to consider.
One option is to use a service provider who routinely collects the required measurements. Scheduling the sampling and keeping control of the data and measurements can become difficult if there is not a good quality agreement in place.
The more favourable solution is a multipurpose instrument that can be used for other environmental samplings. The instruments are available in-house and need to be kept in a validated stage with an associated repair and maintenance scheme; the only additional costs are those of the accessories needed for sampling.
About the authors
FRANK PANOFEN, PhD, is Sterility Assurance/Microbiology Product Line Manager, at Particle Measuring Systems. Dr Panofen has a Diploma in Chemistry from the University of Bielefeld and a PhD in molecular and cell biology from the University of Osnabrück. He has been an invited speaker at international conferences including ECA and PDA, with a strong regulatory background in pharmaceuticals. Dr Panofen is a certified Microbiological Laboratory Manager from ECA.
DANIELE PANDOLFI is Global Product Specialist, Aerosol, Life Science Division, at Particle Measuring Systems. Mr Pandolfi has over 11 years’ experience in particle counter instrumentation and cleanroom contamination control. He has been responsible for the EMEA Service Department for the last four years and recently moved into the Global Life Sciences organisation.
Hi. I just want to ask if you can give acceptable parameters against dust, oil and water of the compressed air that is blown directly to product packaging material.
For the Monitoring frequency of compressed gases after the initial test, the test should be run monthly for six months, and if these results are satisfactory, the test should be performed quarterly for the rest of the first year. After the first year – and if the results are still satisfactory – the frequency can be lowered to twice per year in an ISO 5 area, corresponding to each cleanroom verification performed every six months in Europe, but reduced with good justification to once per year in the US.
Could you please provide any reference or guidelines that support this programe?
This website uses cookies to enable, optimise and analyse site operations, as well as to provide personalised content and allow you to connect to social media. By clicking "I agree" you consent to the use of cookies for non-essential functions and the related processing of personal data. You can adjust your cookie and associated data processing preferences at any time via our "Cookie Settings". Please view our Cookie Policy to learn more about the use of cookies on our website.
This website uses cookies to improve your experience while you navigate through the website. Out of these cookies, the cookies that are categorised as ”Necessary” are stored on your browser as they are as essential for the working of basic functionalities of the website. For our other types of cookies “Advertising & Targeting”, “Analytics” and “Performance”, these help us analyse and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these different types of cookies. But opting out of some of these cookies may have an effect on your browsing experience. You can adjust the available sliders to ‘Enabled’ or ‘Disabled’, then click ‘Save and Accept’. View our Cookie Policy page.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Cookie
Description
cookielawinfo-checkbox-advertising-targeting
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category "Advertising & Targeting".
cookielawinfo-checkbox-analytics
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category "Analytics".
cookielawinfo-checkbox-necessary
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Necessary".
cookielawinfo-checkbox-performance
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category "Performance".
PHPSESSID
This cookie is native to PHP applications. The cookie is used to store and identify a users' unique session ID for the purpose of managing user session on the website. The cookie is a session cookies and is deleted when all the browser windows are closed.
viewed_cookie_policy
The cookie is set by the GDPR Cookie Consent plugin and is used to store whether or not user has consented to the use of cookies. It does not store any personal data.
zmember_logged
This session cookie is served by our membership/subscription system and controls whether you are able to see content which is only available to logged in users.
Performance cookies are includes cookies that deliver enhanced functionalities of the website, such as caching. These cookies do not store any personal information.
Cookie
Description
cf_ob_info
This cookie is set by Cloudflare content delivery network and, in conjunction with the cookie 'cf_use_ob', is used to determine whether it should continue serving “Always Online” until the cookie expires.
cf_use_ob
This cookie is set by Cloudflare content delivery network and is used to determine whether it should continue serving “Always Online” until the cookie expires.
free_subscription_only
This session cookie is served by our membership/subscription system and controls which types of content you are able to access.
ls_smartpush
This cookie is set by Litespeed Server and allows the server to store settings to help improve performance of the site.
one_signal_sdk_db
This cookie is set by OneSignal push notifications and is used for storing user preferences in connection with their notification permission status.
YSC
This cookie is set by Youtube and is used to track the views of embedded videos.
Analytics cookies collect information about your use of the content, and in combination with previously collected information, are used to measure, understand, and report on your usage of this website.
Cookie
Description
bcookie
This cookie is set by LinkedIn. The purpose of the cookie is to enable LinkedIn functionalities on the page.
GPS
This cookie is set by YouTube and registers a unique ID for tracking users based on their geographical location
lang
This cookie is set by LinkedIn and is used to store the language preferences of a user to serve up content in that stored language the next time user visit the website.
lidc
This cookie is set by LinkedIn and used for routing.
lissc
This cookie is set by LinkedIn share Buttons and ad tags.
vuid
We embed videos from our official Vimeo channel. When you press play, Vimeo will drop third party cookies to enable the video to play and to see how long a viewer has watched the video. This cookie does not track individuals.
wow.anonymousId
This cookie is set by Spotler and tracks an anonymous visitor ID.
wow.schedule
This cookie is set by Spotler and enables it to track the Load Balance Session Queue.
wow.session
This cookie is set by Spotler to track the Internet Information Services (IIS) session state.
wow.utmvalues
This cookie is set by Spotler and stores the UTM values for the session. UTM values are specific text strings that are appended to URLs that allow Communigator to track the URLs and the UTM values when they get clicked on.
_ga
This cookie is set by Google Analytics and is used to calculate visitor, session, campaign data and keep track of site usage for the site's analytics report. It stores information anonymously and assign a randomly generated number to identify unique visitors.
_gat
This cookies is set by Google Universal Analytics to throttle the request rate to limit the collection of data on high traffic sites.
_gid
This cookie is set by Google Analytics and is used to store information of how visitors use a website and helps in creating an analytics report of how the website is doing. The data collected including the number visitors, the source where they have come from, and the pages visited in an anonymous form.
Advertising and targeting cookies help us provide our visitors with relevant ads and marketing campaigns.
Cookie
Description
advanced_ads_browser_width
This cookie is set by Advanced Ads and measures the browser width.
advanced_ads_page_impressions
This cookie is set by Advanced Ads and measures the number of previous page impressions.
advanced_ads_pro_server_info
This cookie is set by Advanced Ads and sets geo-location, user role and user capabilities. It is used by cache busting in Advanced Ads Pro when the appropriate visitor conditions are used.
advanced_ads_pro_visitor_referrer
This cookie is set by Advanced Ads and sets the referrer URL.
bscookie
This cookie is a browser ID cookie set by LinkedIn share Buttons and ad tags.
IDE
This cookie is set by Google DoubleClick and stores information about how the user uses the website and any other advertisement before visiting the website. This is used to present users with ads that are relevant to them according to the user profile.
li_sugr
This cookie is set by LinkedIn and is used for tracking.
UserMatchHistory
This cookie is set by Linkedin and is used to track visitors on multiple websites, in order to present relevant advertisement based on the visitor's preferences.
VISITOR_INFO1_LIVE
This cookie is set by YouTube. Used to track the information of the embedded YouTube videos on a website.
Hi. I just want to ask if you can give acceptable parameters against dust, oil and water of the compressed air that is blown directly to product packaging material.
Literature shared on this website is knowledge enhancing and brain storming.
Production gasses required to be sterile when feeded on to Bioreactors in vaccine manufacturing?
What is the Microbial limit for the compressed gases monitored?
any guideline please.
what the frequency for the microbiological test for gases during sterile manufacture process?
For the Monitoring frequency of compressed gases after the initial test, the test should be run monthly for six months, and if these results are satisfactory, the test should be performed quarterly for the rest of the first year. After the first year – and if the results are still satisfactory – the frequency can be lowered to twice per year in an ISO 5 area, corresponding to each cleanroom verification performed every six months in Europe, but reduced with good justification to once per year in the US.
Could you please provide any reference or guidelines that support this programe?