Stability Testing Roundtable

Wei Pan, Ph.D., RAC
Director, Strategy & Analytical CMC
Catalent Pharma Solutions

Jeffrey A. Wilhelm, Ph.D.
Director, Small Molecule Analytical Chemistry
Catalent Pharma Solutions

Graeme Lowe
Director, Development and Analytical Solutions
Catalent Pharma Solutions

Dr. Orna Dreazen
CEO and Board of Directors' Chairperson
Nextar Chempharma Solutions Ltd.

Martin Whitehouse
Head of Analytics
Aesica Pharmaceuticals

Dr. Paul Marshall
Pharmaceutical Assessor, Licensing Division
MHRA

Dr. Zabin Younes
Stability Services Manager
SGS M-Scan Limited, UK

1. What trends are emerging in stability testing of biologics?

WP, JW, GL: Small biotech companies’ historically bundled stability testing with product manufactures and leave stability storage and testing at the contract manufacturer sites. Often the manufacturing sites do not have the full analytical testing capability, so some tests (e.g. bioassay, peptide mapping) were subcontracted to a third party. In the extreme case, samples pulled from stability were sent to several testing labs to complete the full battery of tests for a single stability point ultimately extended timelines.

Recently, we have seen biotech companies shifting the stability studies from manufacturing sites to other contract labs with comprehensive testing capability for one stop shopping such as Catalent. Since most biologics are expensive to make, consolidating stability testing to one lab can often reduce the amount of samples allocated for testing therefore save money and save time. In addition, biologics samples typically require refrigeration or freezing during shipping. Consolidating stability storage and testing to one facility can minimize the chance for excursion and increase compliance.

ZY:

• There is an increase in testing the stability of molecules, which are highly potent and require stability indicating tests that perform successfully at low product strengths.
• There is an increase in customers testing sub-visible particles early in the product lifecyle in both drug substance and drug product. The data from this supports formulation development and storage/ transport conditions.
• More and more, customers see the value in completing excursion studies upfront to support cold chain excursions. The ideal studies are based on a risk assessment of anticipated shipping routes and focus on high risk excursion areas (e.g. Customs/prolonged agitation for a liquid product).

2. What are the key considerations of establishing a global stability program?

WP, JW, GL: When establishing a global stability program, it is critical to have a comprehensive understanding and stay up to date of the latest regional and individual country stability requirements and expectations for the intended m arket. I n a ddition t o I CH a nd W HO s tability g uidelines, you need a partner that stays current with the ever-changing regional and country requirements. Catalent has a global approach to stability programs with multiple sites in the US and EU and remains up to date on all requirements and regulations. For many companies, this is challenging as some countries change their requirements much more often than the United States. Examples of some changing regulations: 1) Brazil published a new API stability guidance in February 2013, OS (Ordem de Serviço) 02/2013 API Stability. This guidance has a major impact for API manufactured outside Brazil and imported for manufacturing for medical product in Brazil. 2) Brazil also scheduled this year to revise their 2005-published stability guidance (where the long t erm s tability c ondition w as c hanged t o 3 0 ° C/75% R H). 3 ) I n May 2013, ASEAN (Association of Southeast Asian Nations) issued their 5th draft stability guidelines in using ICH zone IVb requirements for long term storage conditions (with individual country exception of Taiwan a nd T hailand). It is also important to look c arefully a t e arly product stability data, the marketing plans, and the regional or country packaging preference to select a packaging that will provide adequate protection. L astly, it is critical to select a service provider with a full storage and testing capability for global registration.

OD: A global stability program should consider the following:

• The geographical distribution of the product hence the climatic conditions, hygienic and physical conditions (culture) of the users.
• The desired length of treatment and availability of the product for the relevant population.
• The shipment and distribution conditions in the different geographical zones.
• The level of education of the consumers (is the drug used under supervision of medical staff or at home?).
• Conditions of keeping the product in use.
• The sensitivity of the product to temperature, light, UV etc.
• Potential degradation product and their effect on the wellbeing of the consumers.
• Product cost.
• The effect of product waste on the ecosystem.

MW: Stability studies represent a vital part of any development program for pharmaceutical products. Aesica typically undertakes stability testing of products for a period of up to 3 years. Potentially a study can extend out to 5 years but the focus of any study is ensuring that we can provide the customer with enough data to assure them of the stability of their product.

In developing a global stability program, a contract development and manufacturing organization (CDMO) such as Aesica, would consider the territory that the product will be distributed to and would design the study with the country or region in mind.

The standard conditions that Aesica would typically test a product in are:

• 25°C/60% relative humidity
• 30°C/65% relative humidity
• 40°C/75% relative humidity

However, there is a tendency in the market to test a product in the extreme conditions, at the top and lower ranges only. This is primarily for cost and time savings, but the number of conditions you can test a product in is also dependent on how many samples are available for testing.

In establishing a global stability program, there is a need to also consider that individual territories may enforce specific packaging requirements and also have certain patient requirements. For example, blister packaging remains a popular packaging solution worldwide as the patient can check how many tablets they have taken.

There are also specific testing requirements for different territories, for example, there may be a requirement by some authorities for triplicate testing rather than duplicate testing of products.

PM: A global stability program should be able to satisfy the regulatory requirements of the Competent Authority where the product is intended to be marketed, whilst minimizing the number of samples and conditions that are tested by the company.

For active substances and drug products marketed in Europe, the regulatory requirements for stability studies are described in the ICH Q1 set of stability guidelines (www.ich.org) and the CPMP set of stability guidelines (www.ema.europa.eu) – both sets of guidelines are applicable.

The specifications (release and shelf life) for the active substance and drug product should also comply with the relevant ICH and CPMP guidelines on specifications and impurities, plus relevant European and national pharmacopoeial standards.

However, the pharmaceutical industry is globalized; active substances, bulk intermediates and finished products or final commercial products can be manufactured and shipped from one part of the world to the other, often through environmentally challenging areas. The global stability program should also consider the environmental conditions encountered within the distribution and supply chain.

ZY:

• Ensuring the test methods across sites are harmonized
• Ensuring the same Quality processes are applied (e.g. OOS/OOT investigations)
• Ensuring the approach to stability studies are acceptable to local regulatory bodies via open communication
• Ensuring appropriate knowledge of product stability upon transportation is obtained prior to shipping product across sites

3. What are the challenges of integrating QbD into stability testing? What are the advantages of doing so?

WP, JW, GL: The extensive number of samples that ultimately translate into extensive resources and increased costs has to be a consideration when integrating QbD into stability testing. By doing this, you have increased knowledge of factors that may impact your stability program.

OD: The current ICH Guidelines for stability studies do not take into account the problematic issues introduced during shipment and distribution as well as by opening of the package of the product.

These issues should be introduced into the studies when QbD is integrated.

For example QbD should be designed to:

• Expose products to the different conditions during long shipment in high temperatures, high humidity etc., and then back to "normal" conditions.
• Exposure of products to changing conditions such as oxidation, humidity light etc. during in use.

The challenge is to consider so many different possibilities in the study in addition to the classical studies. This may result in expensive exercises which may affect product price dramatically.

The suggestion is to study extreme conditions first and include additional studies only if the product failed the "worst case" conditions.

MW: QbD allows the customer to define the accessible design space of the product. By integrating QbD into stability testing, the customer will be provided with a variety of extremes of the product.

From an analytical chemistry perspective, the study would result in a number of different batches, each batch with different characteristics. At Aesica, our team would then assess the stability of each batch. For example, if you have an accessible compression range on a tablet and you compress the product at both the soft and hard end of the range, this would allow you to monitor how this impacts the stability. QbD allows you to consider the future manufacturing process and test the extremes of where you can go with a product.

A matrix approach can be utilized to QbD where consideration would be given to verify if certain manufacturing parameters lend themselves to particular analytical criteria. Again in the example of the compression of a product, a key consideration during a stability test would be the dissolution – so you may not test for all considerations, but focus on the ones you know have a high chance of impacting the stability of the product.

The key advantage of integrating QbD into stability testing is that it provides the customer with a better knowledge of the robustness of the product which will feed into the manufacturing process.

PM: Quality by Design is a developing area and is currently finding applications in the development of active substance synthesis, drug product manufacturing, formulation design and analytical methodology. The knowledge and greater understanding gained by the QbD approach allows a more flexible regulatory approach by approval of Design Spaces.

The same advantages of QbD could extend to stability testing and the setting of the shelf life and storage conditions. To some extent, current regulatory requirements to investigate how temperature, humidity and light influence the quality attributes of the active substance or drug product already integrates QbD principles.

However, the development of any design space must be based on appropriate data, looking at how different input factors affect the quality of the product. This provides the first challenge to a stability design space, in that it may take a considerable length of time to determine how certain environmental factors influence the quality of an active substance or drug product. Formulation, manufacturing and analytical resource are also required to produce and test stability samples.

There have been recent developments, such as the Accelerated Stability Assessment Program (ASAP), which uses a modified Arrhenius equation and elevated temperature and humidity conditions to generate stability data in a much shorter time period, which can then be extrapolated to ICH/CPMP stability conditions and real life storage. The robustness of the model, particularly the extrapolation to real-life storage, presents a second challenge.

However, the QbD approach coupled with accelerated testing methodologies could form part of the pharmaceutical development/risk minimization strategy, increasing the assurance of a stable product when tested in confirmatory regulatory stability studies. The MHRA are looking forward to providing advice and working with companies in developing the use of QbD in the stability area.

ZY: The challenges are building sufficient knowledge space on the same category of a molecule and activity type that provides the business with a platform upon which to design QbD offerings, at a lower cost, with relatively lower risk but that are suitable for a variety of customers. For example there is a vast amount of data available on mAbs, but with an increase in industry testing non-mAbs (BiTE/Fragments/ recombinant subunit proteins), building a molecule-specific database for these other molecules will take time and data.

Another challenge is that, in biologics, even if a molecule is a standard molecule with a standard expected mode of action, upon testing, it may not fit the critical parameters that will allow use of the QbD knowledge space. Therefore development of a stability program of this molecule will have to be comprehensive and historical data on similar molecules cannot be leveraged.

Integrating QbD into stability testing can be accomplished once a suitable design space has been built. Within this space, studies can focus on known high risk degradation routes for the molecule that impact potency. This could also be used to look at more suitable accelerated conditions that may support long term shelf life assignment.

The advantages of QbD will be the ability to prepare moleculespecific study designs where historical fact-based data on the molecule type may be used to focus the study design on areas of high risk. This will also mean an upfront focus on likely stability indicating assays and shipment excursions could be included in standard stability studies. This will reduce overall cost and testing whilst providing valuable data.

4. What approaches are employed to understand and address the impact of temperature on stability, specifically during shipping and transport of products?

WP, JW, GL: In order to understand and address the impact of extreme temperature variation on product stability during shipping and transport, a thermal cycling study should be considered. During thermal cycling study, the packaged product is cycled through temperature conditions simulating those encountered during product distribution. A typical thermal cycling study consists of three cycles of two days at 40 °C/two days at -20 °C. For products labeled “protect from Freezing”, a thermal cycling study consists of three cycles of two days at 40 °C / two days at 5 °C. Samples should be tested at the end of the third cycle, based on the appropriate tests for the product.

OD: Currently little is done. In many instances, the producer is not the distributor and the sales agent; hence the issue is not well addressed. It should be introduced as a joint effort between product owner and distributor based on risk management.

MW: 40°C/75% relative humidity as the accelerated condition is the standard testing for a product. Testing a product at this range will always provide an indication if a short excursion to that type of environment is acceptable and what effect this condition may have on the product.

Typically for the development lifecycle stage that the Aesica Formulation Development team works at, testing at this accelerated condition is sufficient. However, as you move into commercial products, stability studies will cycle through various conditions and will move from a low to high range where the product will be held for a certain time period, before it is moved back down to the lower range and the process may be repeated. To decide if this approach to stability testing is undertaken would be determined by any concerns in regards to shipping and storage of the product. For example, would the product be sitting on the tarmac in the Middle East or Alaska – two extremes that would need to be considered in the design and development of the product? In a recent formulation development study that Aesica has completed to test the stability of the product at the lower range of temperature, a solution was frozen, defrosted and the process repeated to show that the product remained stable and no precipitation had occurred during testing. The process gave our customer the confidence and assurance that the product could withstand such conditions without any detrimental effect should it be shipped to this type of environment.

PM: The mean kinetic temperature of any part of the world can be derived from the climatic data and, for the purposes of ICH and CPMP stability guidelines, the world can be divided into four different climatic zones, I-IV, although climatic zone IV has been further divided into IVA and IVB. Europe is generally classified as climatic zones I (temperate) and II (subtropical/Mediterranean). ICH and CPMP guidance requires the stability of active substances and drug products to be tested in long term or real-time storage conditions as well as at elevated temperature and humidity. Similar testing is also required for bulk intermediates and drug products (see QWP Q&A on Stability issues of pharmaceutical bulk products use in manufacture of the finished product, published on the EMA website). The results from these studies can then be used to set the storage conditions, which should be observed at all times, including transportation, in line with EU Good Manufacturing & Distribution Practice (as published on the EC website, www.ec.europa.eu/health/documents/eudralex, in Eudralex Volume 4 Guidelines for good manufacturing practices for medicinal products for human and veterinary use).

In the real world global environment of the pharmaceutical industry, it is acknowledged that excursions from these storage conditions will inevitably occur. Results from elevated intermediate or accelerated stability conditions can be used to understand the impact of these excursions on the quality, safety and efficacy of the active substance or drug product.

However, it should be recognized that the mean kinetic temperature approach used in ICH/CPMP stability studies does have some drawbacks, for example, the impact of temperature and/ or humidity spikes or cycling is not investigated. Results from stress testing of the active substance and finished product, often carried out as part of analytical method validation, may be helpful in this respect though. Ultimately, worse case simulated transportation studies may have to be undertaken to map out the distribution and supply chain. The marketing authorization holder of the drug product and distributors are ultimately responsible for ensuring products are of acceptable quality, safety and efficacy.

ZY: The best approach is to first identify a worst case distribution plan representing the highest number of stop points across the greatest expected distances. Then, identify areas of high risk excursions (i.e the stop points/customs/agitation during shipping of a liquid for an extended period) and anticipate the worst case excursions taking into account the local environmental conditions (e.g. excursions to -20°C in colder climates or up to +50°C/35% RH in hotter climates). With this information, a study focusing on shipment and transport conditions for the product can be established. This can be phased in early development where a much smaller study can be set up supporting early clinical trial routes, this can subsequently be built up supporting pre-license activities.

5. What future challenges do you foresee in stability practices for commercial products?

WP, JW, GL: We anticipate there will be a number of challenges impacting stability programs for commercial products in the future. The need to have multiple labs complete programs and manufacturing increases costs. With ever-changing regulatory requirements in various countries, outsourcing to a lab that has not only broad capabilities but also global support, can help reduce these costs.

OD: The major challenges in stability studies are:

• Studying stability using validated stability indicating methods from the early developmental phases.
• Designing the studies to consider the different aspects of storage, distribution, storage at the different sites before use and in use.
• Designing cost effective studies to avoid increase of product price. This could only be based on risk management and not on nonfl exible guidelines.
• Following market habits in the different areas and revisiting the stability studies to include additional conditions that were not considered earlier.

MW: A future challenge in stability practices for commercial products will be the changing world environment. The ICH Guidance was established between the USA, Europe and Japan and the standard storage conditions were set with these regions in mind with 25°C/60% as the medium environment conditions. However, as products move to be distributed on a global rather than regional scale, and are exposed to more extreme conditions, those practices may change to push those standard conditions out, so it may be that 30°C/65% becomes more of a ‘standard’.

In the future, regions and countries may have specifi c storage requests aligned to their own climates, e.g. Middle East authorities may request products to be tested at a certain temperature that refl ects the climate in the countries the products will enter. This could also be overcome by storage of products in refrigeration but we expect the individual territories will demand ambient storage.

PM: It is widely accepted that stability testing of active substances and drug product can be costly, in terms of time and resources. The challenge to commercial companies is to reduce this time and cost, whilst still generating regulatory acceptable data on how the quality, safety and effi cacy of their active substance or drug product is infl uenced by environmental factors.

The MHRA can provide advice on general or specifi c product related stability matters, and will actively work with companies to meet these challenges.

ZY: For biologics, there will be challenges brought with the next generation of products; namely biosimilars and biobetters. In order to gain an edge in the market, these products could be developed with increased stability and/or with easier to administer dosage forms or devices. To gain a competitive edge, clients will demand more rapid performance of forced degradation and stability studies, as part of a comparability package.

6. Any closing thoughts?

WP, JW, GL: Stability is a critical quality attribute of pharmaceutical products.

Stability testing is a regulatory and compliance requirement throughout the entire product development cycle and commercialization. Today, more and more companies are targeting the global market for their products. This creates new challenges and offers collaborating opportunities for both Pharma and biotech companies as well as CROs.