In parenteral sterile fill-finish manufacturing, drug products must be free from viable microorganisms – critical for products administered via injection or other routes where sterility is paramount. Consequently, the production process involves aseptic techniques and sterilisation to ensure sterility and mitigate the risk of contamination. As a result, the pharmaceutical industry faces stringent regulations to ensure drug product safety, efficacy, and quality.
However, the global regulatory landscape is constantly evolving so the challenge for manufacturers is maintaining regulatory compliance and keeping the supply chain flowing to deliver life-changing therapies to patients.
Challenges in sterile manufacturing
There are several key areas that drug manufacturers should focus on to meet best practice and compliance in relation to global regulations and sterile manufacturing.
The most mission-critical challenge is maintaining stringent sterility and contamination control to best ensure product safety. Compliance with current good manufacturing practice (cGMP) and updated regulatory standards including Annex 1 is a significant requirement for sterile drug product manufacturing facilities overseen by national and/or international regulatory authorities.
“Annex 1 is your entry point to what’s required; it sets the minimum standards,” says Tom McGrath VP, Global Quality for Development & Manufacturing at PCI Pharma Services, a leading global contract development and manufacturing organisation (CDMO) with over 30 sites across the world. PCI recently built a best-in-class facility in Bedford, New Hampshire, for large-scale sterile fill-finish and lyophilization. With future proofing in mind, and by following industry best practice and a bottom-up approach, PCI confronted regulatory issues head on.
According to McGrath: “We went above and beyond when we designed the facility. We added features, scaled everything, and worked to tighter specifications including a grade-C background for the isolator. We put additional control measures in place as best practice – from gowning to cleaning – which has allowed us to outpace the Annex 1 standards.”
Sterile manufacturing processes require aseptic techniques and/or terminal sterilisation technologies to make certain that the manufacturing environment retains this high standard, and products are free from viable microorganisms.
To counter regulatory changes and improve contamination procedures, PCI follows very stringent guidelines regarding control and aseptic environments:
“We have extremely strict guidelines of what we allow in the facility and what we don’t. Our first rule is barrier to entry. There are certain classes of drugs that we will not handle in the Bedford facility – there are no cellular-based therapies or live/attenuated viruses allowed. The second is that we do not allow shared product contact surfaces; every surface that the drug touches is either dedicated or disposable so there’s no chance of product A contaminating product B,” says McGrath.
PCI’s approach to minimising contamination
On a practical level in a facility, aseptic techniques are used to maintain carefully controlled conditions within a facility to minimize contamination. PCI takes this further by constant monitoring throughout the process. As McGrath states: “Our integrated systems within the isolator allow us to continuously monitor the environment throughout the fill rather than just discrete samples – which was the traditional way of doing it – and allows us to get a greater level of sterility assurance for the product.”
Traditionally, compliance standards are maintained through various means – washing, using sterilised equipment, working in clean environments, and employing PPE barriers, along with terminal sterilisation methods such as autoclaving, and gamma radiation to sterilise products after primary packaging, to avoid contamination until they reach the patient.
PCI practises more enhanced contamination controls that go above-and-beyond regulatory expectations, using single-use technology and mainly gamma-sterilised materials. Furthermore, maintaining a closed system is also part of PCI’s ethos:
“PCI’s philosophy is to keep everything as closed system as possible to prevent contamination. On top of that, also having the proper engineering controls to ensure that you’re not experiencing a loss of product containment when formulating the product,” says McGrath.
When PCI built the latest facility at its New Hampshire Sterile Fill-Finish and Lyophilization campus it included the most advanced equipment to mitigate contamination risk further:
“The new multi-product facility was designed from the ground up to be compliant with global standards, specifically, to the changes to Annex 1. But the key in sterile manufacturing is always to protect the product from any sort of microbial contamination. We installed the large-scale Groninger aseptic vial filling line and twin 430ft2 GEA ALUS lyophilisers within a SKAN isolator which is state-of-the-art. There’s only seven of them in the world and PCI is the only CDMO with one. The only human interaction is during setup, and then the machine does the work,” says McGrath.
The inclusion of the SKAN isolator added another layer of protection against contamination. As Christopher Hamlin, PCI’s Director of Regulatory Affairs, points out: “The isolator itself creates an environment where it’s completely separate from that outside world – there’s a complete physical barrier from start to finish throughout the entire process. Isolators are becoming a cornerstone of modern aseptic processing,”
A risk-based approach
Compliance with quality standards is set by the regulatory authorities and covers all aspects of production, from starting materials to the final product to meet the required specifications. However, PCI uses a risk-based approach within the facility to help plug any regulatory gaps. As McGrath states: “The root of PCI’s robust quality system is that everything must be risk-based and assessed to ensure compliance. This starts with our system design and follows through with our validation, processes, and internal auditing procedures.”
Moreover, to evolve with compliance trends, PCI places significant importance on feedback from client inspections: “As a CDMO, we are constantly being inspected by our global clients, and held to different standards every day. It’s using that feedback loop from different sets of eyes, that helps us to evolve our systems and meet growing needs and industry trends,” says McGrath.
Regular inspections by regulatory authorities ensures ongoing compliance with GMP standards, and compliance with various regulatory jurisdictions to ensure drugs reach all potential markets – noncompliance can lead to the discontinuation of drug development or manufacturing operations. To safeguard against this type of risk, PCI takes a two-pronged approach. “In the US, we get inspected probably once a year by the FDA,” says McGrath. “But for the supply of drug product to clinical sites in Europe, the QPs [Qualified Persons] from the EU and the UK certify each clinical batch, and they hold us directly to Annex 1 – by the letter – as does our internal QP. We also have retained some help from ex-FDA inspectors to come in and pressure test us so that we’re successful in any regulatory inspection, no matter what region of the world it is relating to.”
More recently, PCI successfully completed the International Coalition of Medicines Regulatory Authorities (ICMRA) inspection of its Bedford, New Hampshire campus. “We are honored to have been the first CDMO chosen for the ICMRA’s pilot program, enabling global regulatory agencies to conduct their approval processes simultaneously,” says Hamlin “This collaborative approach and gaining simultaneous approval from multiple global regulatory agencies is a game-changer for the pharma industry, streamlining the path to full-scale sterile drug production and commercialization.”
Countering regulatory issues in the future
Compliance with evolving global regulations in sterile manufacturing is a complex but essential aspect of pharmaceutical production. However, as the regulatory landscape becomes more harmonised region to region, drug manufacturers should look to be ahead of the curve and invest in building robust quality management systems and modernise manufacturing facilities towards automated, closed manufacturing technologies to not only enhance sterility assurance but also improve efficiency to meet future regulatory demands and ensure the delivery of life changing therapies to patients.
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