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Industry experts discuss the challenges and regulations of setting up a CGMP-compliant stability testing program.
BioPharm International spoke with Bhroma Patel, head of product stability, and Baldev Jogi, lead scientist, both at Lonza; and Will Hatcher, senior manager, QC, and Rekha Patel, director, biologics analytical solutions, both at Catalent, about what steps companies need to take when setting up a current good manufacturing practice (CGMP)-compliant stability testing program for biologics.
BioPharm: What are the first steps for setting up a CGMP-compliant stability program for biologics?
Hatcher (Catalent): The first step in setting up a CGMP-compliant stability program is to determine the analytical assays that are stability-indicating and to verify that the method qualification/validation has been performed appropriately to prove that these assays are indeed stability-indicating. After the analytical assays are determined, the next step is to set up the stability strategy, which will include long-term stability at the determined storage condition, short-term stability (accelerated and stressed), and possibly photostability or freeze/thaw studies. It is very important to be conservative with regards to timepoints within a stability study. If the appropriate amount of data [are] not gathered at the appropriate conditions, then it is possible that an entire study would need to be repeated, which becomes extremely time-consuming and costly, and could be detrimental to a regulatory filing timeline.
Bhroma Patel and Jogi (Lonza): An amendment agreement is required between the clients and outsourcing company to see what stages of work [are] required from start to end. This will include objective, activities (e.g., timepoints, temperatures, and intended storage temperature), test methods, and delivery of reports. In addition to this, methods and equipment require validation and specifications put in place prior to starting the stability study.
BioPharm: What challenges should companies be aware of when setting up a CGMP stability program for biologics?
Bhroma Patel and Jogi (Lonza): The challenges companies must be aware of when setting up the GMP stability programs are that regulatory requirements, such as the ICH [International Council for Harmonization] guideline, are followed throughout the stability program, from pilot stability studies to drug product studies. Companies may require large facilities for laboratory capacity, storage, as well as stability chambers under different climatic conditions and relative humidity and freezers. In addition, companies are required to develop, validate, and evaluate testing methods and equipment to perform stability studies.
Rekha Patel (Catalent): Companies should ensure that they have redundancies in power, water, and air handling systems as well as appropriate alarm notification systems, to safeguard against possible impacts to the study. To ensure integrity of the study, sample traceability and inventory systems should also be in place. Having a sufficient volume of materials should not be overlooked. Study coordinators should ensure that they have enough materials to progress through the study as well as any investigations or extensions. If special studies are needed, such as freeze/thaw, in-use, forced degradation studies, photostability, etc., proper material amounts should be ensured as volume is often a challenge.
Study coordinators should ensure that methods are proven to be stability-indicating during qualification/validation, are appropriately set up beforehand, and that orthogonal methods are available where appropriate. Analytical methods may change going from early to late phase (e.g., moving from ELISA [enzyme-linked immunosorbent assay]-based to cell-based), and investigators should plan for any bridging activities that may be needed. Appropriate planning also includes a thorough understanding of the study matrix and any special handling required. The timing of the study should be laid out to meet any critical regulatory filings. If planning to file globally, consider testing conditions specific to different regions in the same study, as this will provide sufficient data without the time and cost needed to conduct a separate study.
BioPharm: What are the specific regulatory requirements for a CGMP-compliant stability program?
Bhroma Patel and Jogi (Lonza): The specific regulatory requirement for stability programs for biologics are defined in ICH guidelines with reference to ICH Q1A (R2), Stability Testing of New Drug Substances and Products, ICH Q5C, Stability Testing for New Dosage Forms, and EMA/CHMP/BWP/534898/2008 rev. 1 corrigendum, Guideline on the Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials. For recommendations on how to establish shelf life or retest period based on stability studies, ICH Q1E, Evaluation of Stability Data, is followed. In total there are six ICH basic guidelines for stability studies, Q1A to Q1F.
Hatcher (Catalent): The regulatory requirements for CGMP stability programs mainly come from ICH guidelines, specifically: Q7 11.5, Q1A (R2), Q1B, Q1C, Q1D, Q1E, Q5C. There are also regulations from the FDA (21 Code of Federal Regulations 211.166) and European Medicines Agency (EMA) (Guideline 3AB5a) that govern what should be contained in a stability strategy. In addition to these regulations, FDA provides guidance that can help determine an appropriate stability study strategy.
With this bolus of information, it can be challenging to determine a clear stability strategy. However, as long as the assays performed are stability-indicating and the stability strategy includes long-term at storage condition, accelerated and stress stability studies, in most cases this can be enough for an initial filing. As a product moves through the clinical lifecycle, photostability and freeze/thaw studies will need to be performed. Additionally, depending on the properties of the product and the results of the stability studies, additional studies may be warranted.
BioPharm: Can you provide an example of how a company can ensure their stability program is following regulations?
Bhroma Patel and Jogi (Lonza): Companies can ensure [the] stability program is following regulations by [creating] standard operating procedures (SOPs) to help set up stability studies and protocol in compliance with regulatory expectations.
[A] stability program should be described in the protocol to support the shelf life and storage condition and include:
BioPharm: Can you provide any examples of mistakes companies have made when preparing stability studies for investigational new drug (IND) submissions?
Bhroma Patel and Jogi (Lonza): As a CDMO [contract development and manufacturing organization], the biggest issue we encounter is often around data. For example, companies provide insufficient data and information to support stability of drug substance or information is erroneous due to lack of time to prepare for IND submission. Failure to follow FDA guidance or to summit all the information required from the IND submission checklist is another potential oversight.
Hatcher (Catalent): The main mistake that companies make when setting up their stability strategy is not performing accelerated, stressed, photostability, or freeze/thaw stability studies. Often, a process will change throughout the clinical development of a product, and with these changes comes the need to repeat stability studies. I have seen a trend where companies will not repeat the accelerated or stressed stability; however, they will repeat standard stability at the storage condition for the product. This is a very risky strategy, as regulators will want data to show that the change in the process did not impact the stability of the product, including stressed and accelerated stability studies.
BioPharm: What are the benefits of outsourcing CGMP stability studies for biologics?
Bhroma Patel and Jogi (Lonza): Companies have access to regulatory experts and can meet the most up-to-date regulatory requirements. Companies can meet their needs and requirements (planning and designing stability studies). [There is] cost saving, as large amount of capital is not required on resources, such as on analytical equipment and stability chambers. [They can] gain scientific and analytical knowledge for data generation, interpretation, and reporting. [Outsourcing] enables companies to focus internal resources on new drug discovery and development.
Hatcher (Catalent): The main benefit of outsourcing CGMP stability studies for biologics is that CMOs are exposed to many different strategies from sponsors and, therefore, have a good handle on trends in the industry. This level of expertise can be very beneficial for the sponsor and will ensure that the stability program is compliant and up to date with trends in the industry. Another benefit is the analytical expertise that CMOs possess because the analysts in a QC [quality control] CMO laboratory are familiar with several types of analytical methods, which means CMOs are well placed to help the sponsor troubleshoot methods to make improvements when there are issues.
Outsource facilities also typically have significant storage space and analytical instrumentation. This helps the sponsor know that there will not be equipment or space constraints that could negatively impact their stability program.
BioPharm: What are the challenges of outsourcing CGMP stability studies for biologics?
Hatcher (Catalent): The main challenge from a CDMO perspective is when a sponsor changes the stability strategy late in the game. This can be detrimental to the timeline and ultimately could delay approval. Another challenge is balancing cost-savings versus performing stability using a conservative approach. There are times when a sponsor is focused on cost-savings and then limits the stability program, only to have to come back later and perform the study again. This is why it is very important to perform the study in a conservative manner, to avoid having to repeat.
Bhroma Patel and Jogi (Lonza): Finding a trusted outsourcing partner with the right level of expertise and process knowledge, as well as the right assets and technology is key. Without this, delivery may be late or below expectations, leading to a delay in progressing drug production to the next level. Confidentiality and security are essential to avoid breaches of proprietary information in a multi-customer facility.
Lastly, a strong track record of quality compliance and experience working with regulatory bodies in different jurisdictions is also paramount.
BioPharm: How can a sponsor company ensure their outsourcing facility is following CGMPs?
Bhroma Patel and Jogi (Lonza): Companies should conduct site audits to verify outsourcing best practices and standards of GMP. Also, to check validated systems and processes, and that staff are experienced and properly trained. Checking the FDA, MHRA [Medicines and Healthcare products Regulatory Agency], etc., history of an outsourcing partner as well as the QA procedures in place ensures that an established culture of regulatory compliance and high standards exists.
Hatcher and Patel (Catalent): When outsourcing stability studies, it is important to ensure that the contract provider can meet regulatory requirements. One way in which our company helps reassure clients about CGMP compliance is through on-site customer audits, where auditors can dig into the procedures and processes and verify that appropriate regulations are followed. Having the outsourcing facility provide raw data to the client is also an excellent way to provide transparency and confidence in CGMP compliance.
When working with an outsourcing facility, on-site audits should be performed prior to setting down any studies. In addition, the sponsor should ensure that the stability chambers to be used for the study are on site at the provider location. Lastly, the site’s regulatory history should be reviewed to confirm that the site has received approval from all relevant regulatory agencies.
Vol. 32, No. 9
When referring to this article, please cite it as S. Haigney, "Best Practices for Studying Stability in Biologics," BioPharm International 32 (9) 2019.