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Obstacles to compliance
BioPharm: What challenges do you see in complying with FDA’s CGMP regulations for biopharmaceutical manufacturing?
Smith (Catalent): In general, it is not difficult to comply with the FDA’s GMP regulations, but there are some nuances that can present a challenge. For example, it is straightforward to complete gap assessments and ensure procedures align with the various laws, guidances, and technical publications that make up current CGMPs.
However, the source documents outlining CGMPs are often written at a high level to allow flexibility in implementation to ensure that the expectations are effective for a broad range of products. While generally easy to understand, the interpretation of the guidelines, especially when there is room for flexibility, can create the potential for challenges.
Having an effective feedback loop from multiple sources, such as regulatory inspections and customer audits, makes it easier for companies to continuously improve their CGMP practices. I have also found that focusing on the patient and product quality outcome are the best guides for appropriate paths forward.
Cohen (Lubrizol): There are various regulations and guidelines around the world regarding the manufacture of biologics, which include information about control of feedlots and cell lines. These address much of the obvious concerns such as potency, safety, and containment. There is less guidance, however, on how to formulate and develop a more complex biological drug product as you reach the finished dosage manufacturing stage.
The amount of complex formulation work involved in biologic products is highly challenging. There is an underlying assumption in regulations that most biologics are destined for simple filtration and sterile fill, with little attention given to non-traditional, more complex dosage forms.
Biologics are complicated to work with because they come from living materials, which have inherent variability. Therefore, the biggest challenge from a GMP perspective is maintaining consistent product quality, as this is dependent on the incoming raw material as well as manufacturing processes. When you add in further complexity, such as a non-traditional dosage form, [consistency] becomes increasingly difficult.
Muzzin (Emergent): Complying with FDA’s GMP regulations for biologics isn’t a challenge per se. The industry has a good understanding of the importance and need for operating in accordance with CGMPs. The challenges lie in how a sponsor’s approach may be interpreted by FDA in meeting the GMP regulations for some biologic products and/or in specific scenarios where advanced manufacturing (i.e., new medical product manufacturing technologies that can improve drug quality, address shortages of medicines, or speed time-to-market) considerations are at play. This situation is demonstrated best in biologics with emerging technologies where novel and innovative approaches are utilized and is evidenced by a new guidance being published on topics such as continuous manufacturing and creation of the CDER’s [Center for Drug Evaluation and Research] Emerging Technology Program and CBER’s [Center for Biologics Evaluation and Research] Advanced Technologies Program.
In addition, for the first time in the history of drug development, with the introduction of regenerative medicines and cell therapies, sponsors are often able to demonstrate efficacy very early on in the product’s lifecycle. This early demonstration can lead to an expedited timeline for commercial filings but leave a truncated manufacturing development timeline and/or limited manufacturing experience compared to the traditional or legacy drug development process where a phased approach to GMP-manufacturing development through Phase I to III of a product historically existed. This [expedited timeline] drives the need for early and continuous engagement with the agency to ensure transparency and shared understanding of risk-based, scientifically sound approaches being leveraged to ensure quality. Sponsors must be able to demonstrate a robust understanding of their product and process early on in development.
BioPharm: What are the struggles you have encountered when trying to comply?
Cohen (Lubrizol): The greatest struggle is achieving adequate characterization of the biologic material. The actual manufacturing process is the bedrock of what we do, but to do it correctly, you must properly characterize your product to ensure consistency, safety, and potency.
With a single entity like a small molecule, characterization is straightforward, and we can utilize methods such as impurity profiling to give an accurate quality overview. However, complicated biologic mixtures are not single entities, so they are much more difficult to fully characterize. Even the initial step of developing the right methods to prove that you have a consistent product is challenging.
Muzzin (Emergent): One industry challenge is the need to continuously strike a balance between providing continual supply of products to the market with the approved facility and/or equipment while also looking for opportunities to maintain GMP compliance, operate in a state of control, and improve aging facilities. Improvements and transition to new technologies take time and often require prior approval from global health authorities, which can present supply-chain challenges and may have implications on drug availability. One example is the transition from conventional fillers to newer isolator technology.
Smith (Catalent): The biggest struggle we, as a manufacturing partner, have encountered is ensuring there is a consistent approach that works for all sponsor companies, while still complying with CGMPs. Problems can arise when different sponsor companies have different requirements for their quality systems, or if their requirements differ from Catalent’s requirements.
In manufacturing, it is important to use consistent, repeatable processes. Catalent is generally able to avoid the conflict between different sponsors’ specific requirements and its internal procedures by having systems clearly state the minimum requirements to meet CGMP, which then allow ‘add-on’ requirements to meet specific sponsor requests.
Best practices for compliance
BioPharm: Are there any ‘best practice’ advice or tips you can recommend for new organizations (e.g., at a start-up), specifically on how to practice and comply with GMPs?
Muzzin (Emergent): It is important to stay abreast of the latest guidance from FDA and other regulatory agencies. To ensure a robust understanding of your product and process, engage early, with specific questions and information, with the agency. If the technology being leveraged is new or novel, be ready to display a deep understanding of the technology and its appropriateness for use with your product or process to the agency.
Smith (Catalent): The most effective quality system is one that can be executed repeatedly and consistently, right the first time, every time, which is made possible when all aspects of the quality system are simple.
By having this simplicity within the quality system, it enables a company to pursue excellence, allowing it to ensure the highest quality products. To do so, the manufacturing company needs to have a thorough understanding of each product manufactured at its site. When a company can design processes that consistently meet all product quality attributes, then this not only meets the base expectations provided in the GMP regulations, it is actively pursuing excellence to ensure quality products.
Lastly, I would recommend that when processes and procedures are designed, it is with technology in mind, doing anything that can be implemented practically to protect products and data, because it is very difficult to make changes after products are already approved.
Cohen (Lubrizol): First, you should really get to know the regulatory requirements and become well versed in them, especially if you want to be globally compliant. Do a thorough review, not only of the requirements set out by FDA and other regulatory bodies, but also the World Health Organization’s comprehensive set of annexes related to biological products.
Second, ensure that you have a strong analytical team working with you, whether that’s internally or through a partnership with a CDMO. The equipment and methods for biologics analytical work are very different to that of small molecules, and it’s important to have access to the instrumentation and analytical techniques required.
Finally, know the source of the material that is entering your facility, and ensure that the correct manufacturing procedures have been followed to avoid the risk of contamination. Biologic materials are typically manufactured from cell lines that have the potential for forming viruses, and it’s important to understand the viral clearance process that they’ve gone through prior to entering your facility.
Gaps in GMPs
BioPharm: Where are the gaps in GMPs where guidance is still needed?
Cohen (Lubrizol): Further guidance is still needed on quality control and analytical methods. There is a brief reference to these topics in current guidelines stating that the methods should be validated and documented, but there is not much in the actual GMP [regulations], perhaps because these methods are more challenging than a typical high-performance liquid chromatography. In addition, there is not a lot of guidance on how to handle mixtures of materials and what constitutes an appropriate method validation, especially for complex dosage forms which may contain other inactive ingredients.
As a company, when it comes to biologics, we are currently reviewing all the latest regulatory guidances that might be applicable to us, not only from FDA but also from other regulatory agencies around the world. This will result in a high-level policy that will become part of our core processes at Lubrizol Life Science Health.
Smith (Catalent): The GMPs describe minimal guidance by design to ensure that they are enduring and applicable to many products. I wouldn’t say there are specific gaps from my perspective; however, I would like to see a path to introduce new technologies more quickly. Specifically, the ability to use comparability data to implement new technologies with limited regulatory burden would be helpful to ultimately improve the quality of products. While there are some provisions incorporated into the regulations, in practice, any meaningful change requires prior approval and can therefore take years to implement.
Muzzin (Emergent): Opportunities exist in harmonizing, sharing, and training of regulators, innovators, and manufacturers on how to interpret and operate under CGMPs. Compliance and quality should be differentiated. Compliance should be black or white. One facility cannot be more or less compliant than another; you either meet the requirements or you don’t. Quality, however, is about value provided to the customer and can be graded on a scale. With the right quality culture and common compliance playbook, regulators, innovators, and manufacturers can minimize subjectivity and close gaps on defining what it truly takes to ‘operate in a state of control’ per CGMPs.