Susan Haigney

 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.

 What are the first steps for setting up a CGMP-compliant stability program for biologics?

 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.

 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.

 What challenges should companies be aware of when setting up a CGMP stability program for biologics?

 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.

 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. 

 What are the specific regulatory requirements for a CGMP-compliant stability program?

 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

, 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, 

, is followed. In total there are six ICH basic guidelines for stability studies, Q1A to Q1F.

 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 

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.

Can you provide an example of how a company can ensure their stability program is following regulations?

 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:

		Objective/scope of the study (e.g., the stability study results may form part of submissions to the regulatory authorities to support the use of the product in toxicological studies and clinical trials).

		Storage conditions (e.g., intended, accelerated, and stress storage conditions)

		Sampling plan (e.g., samples to be tested at 0, 3, 6, 9, 12, 18, 24, and 36 months)

		Stability indicating parameters for testing of product characteristics, identity, potency, purity, and safety, which have been developed and validated

		Stability test methods (e.g., capillary electrophorsis sodium dodecyl sulfate [CE SDS], image capillary isoelectric focusing [icIEF], gel permeation chromatography [GPC], ELISA), which have been qualified for usage

		Acceptance criteria (e.g., limits for the test results)

		Reference standard to compare the sample against

		Approval process (e.g., approved by quality assurance [QA])

		Stability chambers are serviced, inspected, calibrated, and qualified regularly

		Out of specification and out of trend SOPs

		Evaluation of the acquired data to provide a shelf life

		Trained operators, which includes GMP training and data integrity training annual.

 Can you provide any examples of mistakes companies have made when preparing stability studies for investigational new drug (IND) submissions?

 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.

 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. 

 What are the benefits of outsourcing CGMP stability studies for biologics?

 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.

 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. 

 What are the challenges of outsourcing CGMP stability studies for biologics?

 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. 

 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.

 How can a sponsor company ensure their outsourcing facility is following CGMPs?

 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.

 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. 31, No. 10
	October 2019
	Pages: 58-60

	When referring to this article, please cite it as S. Haigney, "Best Practices for Studying Stability in Biologics," 

Articles

Industry experts discuss the challenges and regulations of setting up a CGMP-compliant stability testing program.

Best Practices for Studying Stability in Biologics

Critical quality attributes (CQAs) are used in biopharmaceutical development to gain an understanding of a product and the processes used to make that product. The International Council for Harmonization (ICH) Q8 (R2) defines CQAs as “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials), and drug product” (1). While CQAs of small-molecule drugs can affect the purity, strength, drug release, and stability of a drug, the complex nature of biologics can create additional quality attributes that can affect the safety and efficacy of the biologic (2). Identifying CQAs for biologics can, therefore, be a complicated process. 
	
	

 spoke with Tapan Das, head of stability, methods and analytical development at Bristol-Myers Squibb and Finance Committee member and past-chair of the BIOTEC Section at the American Association of Pharmaceutical Scientists (AAPS), about how CQAs for biologics differ from CQAs for small-molecule drugs and how they can be determined.

 Are there specific challenges to identifying CQAs in biologics when applying quality by design (QbD)?

 Knowledge-based design, as opposed to a heuristic approach, is a key principle of QbD. Determination of criticality of process and quality attributes improved significantly in the past decade with the advancement of knowledge in protein engineering, biology, and cell culture engineering. However, challenges remain, specifically in establishing criticality, when an attribute has the potential to impact a multitude of factors in the broad category of safety and efficacy. Protein modifications (such as post-translational modifications) and degradation products may affect potency as well as secondary pathways such as altered clearance or induction of immunogenicity.   
	
	

 For recombinantly produced biologics, special attention is paid to the cell culture and purification process parameters as well as storage conditions because of their influence on heterogeneity commonly observed in biologics. It is the heterogeneity in biologics that makes the process of defining criticality of each heterogeneous species extremely challenging. Therefore, consistency of product quality becomes even more important for biologics. 
	
	

 What is the process for determining risk, specifically for biologics?

 Risk assessment is an evolving process from the discovery phase to clinical stages to product approval and commercial manufacturing. In the early discovery and development stages, criticality determination of each process parameter and quality attribute is not meaningful, rather the emphases are on establishing safety and biological function of the product and producing them in a consistent manner. When developing a commercial process and formulation, appropriate analytical, structural, and biological assays are developed that are capable of studying the components in a heterogeneous biologics product, and understand its impact on function, safety, stability, microbiological safety, and dosage form integrity. 

 What tools can be used to determine CQAs for biologics? 

: Criticality determination relies on understanding probability of occurrence and relevance of a given attribute or process parameter; identifying product variants, understanding its biochemical/biophysical properties, and establishing its link to process parameters; and studying impact on function (e.g., binding potency, clearance, antibody-dependent cell-mediated cytotoxicity [ADCC], etc.) and safety (toxicity, immunogenicity). As noted above, it is impractical to study all possible attributes of process and product in early stages to understand, at an individual level, its impact on function and safety.

 Do some studies/tools work better than others? Why?

 This is an important point. Establishing appropriate analytical/biophysical/functional tools that are fit-for-purpose for sensitivity and specificity is key to ensure the known/hypothesized impacts (on structure, function, and safety) can be studied objectively. For example, during commercial development, enrichment studies can be conducted to study impact (and hence, criticality) of one variant at a time. Another example is use of state-of-the-art higher order structure tools, when needed (not suitable for routine use), to deconvolute structural impact from multiple degradations (e.g., oxidation, isomerization) occurring at the same time (3). 

 Are the regulations for CQAs and QbD different for biologics? If yes, how? 

  The ICH guideline [(ICH) Q8 (R2)] is commonly followed for CQA approaches and its use toward establishing a robust manufacturing process. Adoption of QbD differs greatly across regions including within the United States. However, the underlying principles of QbD (i.e., a systematic approach for product and process understanding and process control, based on sound science and quality risk management) towards developing robust process and product are increasingly used across regions. 

 As biologics become more popular in the industry, are companies paying more attention to risk assessment and QbD for these products?

  Generally, yes. Risk assessment still differs significantly across organizations. The past decade has experienced a tremendous growth in the biologics portfolio of the biopharmaceutical industry. With the advancement of knowledge in analytical sciences, protein engineering, biology, and cell-culture process, it is now possible to assess quality attributes more objectively than before. The awareness for the importance of CQA assessment and its critical role in developing robust process/product is also increasing. 

 (ICH, August 2009).
	2. A. Rathore, A. Reason, and A. Weiskopf, 


	Vol. 41, No. 4
	April 2017
	Pages: 50-51

	When referring to this article, please cite it as S. Haigney, "Critical Quality Attributes Challenge Biologics Development," 

The complex nature of biologics adds additional CQAs that must be determined to ensure the safe development of biologics