A study that analysed QA/QC incidents at several biomanufacturing plants has revealed how companies can best hope to detect and mitigate virus contamination.
An entire sector within the pharmaceutical and biopharmaceutical industries is dedicated to ensuring the high quality of drugs. If there are impurities or mistakes made during the medicine-making process, then patients who administer the drugs can face potentially fatalistic consequences.
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.
To prevent this from occurring, quality assurance and quality control (QA/QC) processes need to be strict. However, there remain incidents when these can fail and contamination in manufacturing plants can happen.
Analysis of protein drug contamination
An MIT-led consortium conducted a study which analysed several incidents at manufacturing plants where protein drugs became contaminated with viruses. According to the researchers, these were all discovered before the drugs reached patients, but many led to costly clean-ups and in one instance, a drug shortage.
While the study focused on biopharmaceuticals, the researchers say the findings could also help biotech companies to create safety guidelines for the manufacture of new gene therapies and cell-based therapies, many of which are now in development and could face similar contamination risks.
…viral safety is best assured through complementary approaches”
The study, published in Nature Biotechnology, offers insight into the most common sources of viral contamination and makes several recommendations to help companies avoid such incidents in the future.
Speaking to European Pharmaceutical Review, lead author of the study Paul Barone, co-director of MIT’s Center for Biomedical Innovation’s (CBI) Biomanufacturing Program and director of the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB), said: “From a product safety perspective, detecting a virus contamination is one piece of a broader approach to ensuring a protein therapeutic is safe. It is important to remember that all parts of this technique work together to ensure final product safety.”
Common causes of contamination
A new study from an MIT-led consortium, which analysed 18 incidents of viral contamination at biopharmaceutical manufacturing plants, offers insight into the most common sources of viral contamination and makes several recommendations to help companies avoid such incidents in the future [credit: Betsy Skrip, MIT Center for Biomedical Innovation].
Therapeutic proteins can be produced using recombinant DNA technology, which allows bacterial, yeast or mammalian cells to be engineered to produce a desired protein. Although this practice has a strong safety record, there is a risk that the cultured mammalian cells can be infected with viruses.
The CAACB, which performed the study, was launched in 2010 after a contamination incident at a Genzyme manufacturing plant in Boston. The plant shut down for about 10 months when some of its production processes became infected with a virus in 2009.
When incidents like this occur, drug companies are not required to make them public unless the incident affects their ability to provide the drug. A team from CBI assembled a group of 20 companies that were willing to share information on such incidents, on the condition that the data would be released anonymously.
The study focused on protein drugs produced by mammalian cells and analysed 18 viral contamination incidents since 1985. These occurred at nine of the 20 biopharmaceutical companies that reported data. In 12 of the incidents, the infected cells were Chinese hamster ovary (CHO) cells, commonly used to produce protein drugs. The other incidents involved human or non-human primate cells.
The viruses that were found in the human and non-human primate cells included herpesvirus; human adenovirus; and reovirus. The researchers suggest that these viruses may have spread from workers at the plants.
“We found that for products manufactured in CHO cells, all of the contaminants were traced back to a raw material as the source. Therefore, implementing additional measures to remove or inactivate virus in higher risk raw materials would be expected to reduce that risk; several companies have taken this approach,” said Barone. “In comparison, all of the viruses that were found to contaminate human or primate cell lines were traced back to operators or the cell line itself. So, in designing any viral safety strategy, it is important to understand the potential susceptibility of the production cell line to different viruses and where those viruses might come from.”
Detection of the contamination
According to the authors, in many cases of contamination, incidents were first detected because cells were dying or did not look healthy. In two cases, the cells looked normal, but the viral contamination was detected by required safety testing. The researchers highlight that the most commonly used test takes at least two weeks to yield results, so the contaminating virus can spread further through the manufacturing process before it is detected.
Some companies use a faster test based on polymerase chain reaction (PCR) technology, but this has to be customised to look for specific DNA sequences, so works best when the manufacturers know of specific viruses that are most likely to be found in their manufacturing processes.
“Where detection speed plays a role is two-fold. Firstly, rapid detection is important to limit the extent of contamination in a manufacturing facility. This has the effect of potentially enabling a swift return to regular operations as it can shorten the time and effort required for the investigation, decontamination and implementation of corrective actions. Secondly, in the case of some cellular therapies, the time between when the final product is manufactured and subsequently administered to a patient is very short (ie, the product has a short shelf life or the patient might die without treatment). In these cases, information on virus contamination is needed as early as possible for informed decisions; however, most current virus detection assays are not able to do this. Therefore, new approaches are needed to enable the rapid detection of virus for these products,” said Barone.
Mitigating risk
Many of the CAACB member companies are exploring new technologies to inactivate or remove viruses from cell culture media before use and from products during purification. Additionally, the researchers say that companies are developing quick virus detection systems that are both sensitive and able to detect a broad spectrum of viruses. The CBI researchers are also developing on several technologies that could enable more rapid tests for viral contamination.
…the findings could also help biotech companies to create safety guidelines for the manufacture of new gene therapies and cell-based therapies”
“Identifying areas and materials that are of high-risk and mitigating those risks to prevent accidentally introducing a viral contamination is imperative. Our data indicates that operators are the suspected source of virus contamination when human or primate cells are used. Therefore, cell and gene therapies that use human cells should prioritise mitigating the risk of virus contamination from operators such as raw material handling, appropriate gowning, aseptic handling, sick policy, open processes, etc,” explained Barone.
A strategy that the report recommends and that some companies are already using is to reduce or eliminate the use of cell growth medium components that are derived from animal products such as bovine serum. When that is not possible, another strategy is to perform virus removal or inactivation processes on media before use, which can prevent viruses from entering and contaminating manufacturing processes. The researchers say that some companies are using a pasteurisation-like process called high temperature short time (HTST) treatment, while others use ultraviolet light or nanofiltration.
“High-throughput sequencing, often referred to as next-generation sequencing (NGS), is one technology that has gotten interest from the industry in recent years and has the potential to address some of the shortcomings of existing approaches. While there is quite a bit of work still needed to ensure NGS is broadly ready for use in the biotech industry, that is one example of a technology with the potential to address this need,” said Barone.
Conclusion
The researchers hope that their study will help to guide manufacturers of new gene- and cell-therapy products. These therapies, which make use of genes or cells to either replace defective cells or produce a therapeutic molecule within the body, could face similar safety challenges as biopharmaceuticals as they are often grown in media containing bovine serum or human serum.
“Our study demonstrated that viral safety is best assured through complementary approaches aimed at reducing overall risk,” said Barone.
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.