Stability is a critical quality attribute of pharmaceutical products and is a function of many factors, including the active drug substance itself, the excipients used within the formulation, the manufacturing process employed and the drug product’s container closure system. The purpose of stability testing is to provide evidence of how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and exposure to light, and to establish a retest period for the drug substance or a shelf-life for the drug product, as well as recommended storage conditions.1 Stability studies are conducted throughout all phases of the drug product’s life cycle; the purpose, regulatory requirements and technical challenges for each study vary depending on the product type, the phase of the program and the intended markets.
Stability Studies during Development and Clinical Phase
Stability studies typically start at the preclinical stage of drug development before an Investigational New Drug (IND) or the Investigational Medicinal Product Dossier (IMPD) has been filed, and usually continue through Phase 1, Phase 2 and Phase 3 to gain further understanding of the product, to support formulation development, and to satisfy the regulatory requirements for clinical trials.
Stability Studies to Support Product Development
In understanding the physical and chemical properties of the compound or formulation under development, factors are considered that can influence the stability of the final packaged drug product. These include the active pharmaceutical ingredient (API), the excipients, the manufacturing process, the packaging process, and the packaging materials used.
To assess the chemical stability of the API, it is beneficial to identify the functional groups and labile centers present as well as the molecule’s susceptibility to factors such as pH, temperature, humidity and light. Forced degradation studies can be particularly useful in providing an understanding of the degradation mechanism. Forced degradation should assess potential hydrolysis of the API under acidic or basic conditions, the effects of heat on the drug substance, the compound’s susceptibility to oxidation, and any possibility of the occurrence of photolysis. The information on the effects of pH will also give valuable insight into what the effects of physiological pH will be once the drug is in the body.
Physical characteristics of the API that need to be considered include the existence of polymorphs and the possibility of polymorphic transitions, as well as the susceptibilities of such polymorphs to hydration or solvation, dehydration or desolvation, and the possibility of crystallization of an amorphous material.
For excipients, the International Conference on Harmonization ICH Q8(R2): Pharmaceutical Development2 recommends that drug substance excipient compatibility be evaluated as part of the design of a stable drug formulation. For drugs formulated as solutions or suspensions, compatibility studies will indicate which buffer to use, and the optimum pH for a stable solution/suspension. For solid products, extensive compatibility studies are conducted with the objective to establish which excipients to use in the intended drug product.
The intended manufacturing process should be designed to improve the drug product’s stability by minimizing exposure to solvents, and by selecting a suitable product-drying temperature and time. Additionally, the stability of in-process materials should be evaluated, and sometimes, final products may be tested to identify critical processing parameters.
Finally, container closure systems (CCSs) play a critical role in product stability. A product’s mechanism of instability should be taken into consideration when selecting the commercial CCSs. For example, if a drug is light or moisture sensitive, the CCS selected should be able to protect the product from the exposure to light or moisture. Unfortunately, the CCS itself can have an unintended negative impact on product stability, and there have been reports of API absorption into, or adsorption onto the container closure materials from various pharmaceutical companies in the past. The potential for leachables from container closure material, or from the glue or ink used in the final packaging of the drug product also needs to be studied.
Regulatory Requirements during Clinical Phase
The regulatory requirements of stability studies to support clinical trials are very limited. The goal is to ensure that clinical trial materials regulatory guidance in this area is rather fragmented across various documents. A summary of these is below:
For Phase 1 clinical trials, the U.S. FDA Guidance for Industry cGMP for Phase 1 Investigational Drugs3 states: “we recommend initiation of a stability study using representative samples of the Phase 1 investigational drug to monitor the stability and quality of the Phase 1 investigational drug during the clinical trial” (i.e., date of manufacture through date of last administration).
Similarly, the European Medicines Agency Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (September 2017)4 recommends that for Phase 1 clinical trials, it should be confirmed that an ongoing stability program will be carried out with the relevant batch(es) of drug product and that, prior to the start of the clinical trial, at the least, studies under accelerated and long-term storage conditions will have been initiated. If possible, the results from these studies should be presented in a tabulated form, as should supporting data from development studies. An evaluation of the available data and justification of the proposed shelf life to be assigned to the IMP under trial should be provided.
For Phase 2 clinical trials, according to the U.S. FDA Guidance for Industry INDs for Phase 2 and Phase 3 Chemistry, Manufacturing and Controls Information,5 a description of the stability performance to support clinical studies should be submitted. This should include a list of the tests, analytical procedures, acceptance criteria, the test time point for each test, the storage conditions, and the duration of the study, which should be long enough to cover the expected duration of the clinical trials.
This FDA guideline also notes that, because of the inherent complexity of many dosage forms, there may be no single stability-indicating assay or parameter that profiles all the stability characteristics of the product. Consequently, the manufacturer should consider the development of stability-indicating analytical procedures that will detect significant changes in the quality of the drug product. The nature of the product in question will determine which tests should be included in the stability testing program.
Finally, the FDA guidance states that the performance of stress studies should be encouraged at Phase 2, because such studies provide critical information governing the choice of stability-indicating procedures to be used in real-time studies.
During Phase 3 studies, stability testing should continue to be carried out to monitor product stability and provide marketing application stability data. Stress studies, if not carried out earlier, should be conducted during Phase 3 to demonstrate the inherent stability of the drug substance, its potential degradation pathways, and the capabilities and suitability of the proposed analytical procedures. Stress testing may be carried out on a single batch of the API. This study should include the effect of temperature in 10 degree increments (e.g., at 50 °C, 60 °C) above the temperature used for accelerated testing, humidity (e.g., 75% relative humidity (RH) or greater) and, where appropriate, oxidation and photolysis of the API. The testing should also evaluate the susceptibility of the API to hydrolysis across a justified range of pH values when in solution or suspension. It is important to understand that these onetime stress studies on a single product batch are not considered part of the formal stability study program. Phase 3 stability studies are often used as the registration stability study but they can be separate studies. To ensure that appropriate data are generated for product registration at the New Drug Application (NDA) stage, a formal stability protocol needs to be developed that satisfies all regulatory requirements.
Stability Studies for Product Registration
In contrast to clinical stability, where there is very limited regulatory guidance, the ICH stability guidelines ICH Q1A(R2) - Q1E provide very comprehensive guidance on registration stability requirements for NDAs in the ICH regions, and it was also adopted by the U.S. FDA for Abbreviated New Drug Applications (ANDAs).6 In addition to the ICH guidelines, pharmaceutical companies interested in a global marketing application should also consult the World Health Organization (WHO) stability guideline7 and with the regulatory authorities of the respective region. When the ICH withdrew its stability guideline Q1F for Climatic Zones III and IV in 2006, it decided to leave the definition of storage conditions in Climatic Zones III and IV to the respective regions and WHO. In the stability guideline that the WHO published in 2009, it split ICH Zone IV into two: Climatic Zone IVA with long-term storage condition of 30°C/65% RH; and Climatic Zone IVB with long-term storage conditions of 30°C/75% RH. Various analyses have been conducted to identify suitable testing conditions for WHO Member States based on climatic data, to enable each Member State to decide on long-term (real-time) stability testing conditions. Those Member States that have notified the WHO of the long-term stability testing conditions they require when requesting a marketing authorization are listed in “Long-term stability testing conditions as identified by WHO Member States”. Compared to ICH stability guidelines, the WHO guideline also provides additional guidance including recommendations on test parameters, storage statements and labelling, coverage for both new and established drug products, and the interpretation of storage statements for products approved in Climatic Zone II, but intended for distribution in Climatic Zone IV.
A new WHO stability guideline8 was published in June 2018 which replaced the 2009 guideline. Readers are encouraged to consult the new guideline when considering global registration.
Stability Protocol
A formal stability protocol is not required for development and clinical stability studies. It becomes a regulatory and compliance document from registration stability and commercial stability. 21CFR 211.166(a) explicitly states:
“There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:
(1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability; (2) Storage conditions for samples retained for testing; (3) Reliable, meaningful, and specific test methods; (4) Testing of the drug product in the same container closure system as that in which the drug product is marketed; (5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.”9
The above should be regarded as the minimum set of requirements for a stability testing protocol: other key elements that should be considered include the purpose for which the sample will be used, for example, whether it represents a drug product for use in a clinical trial, for a NDA or an ANDA application, the intended market for the product; and the name of the product and its dosage strength. Container closures, test methods and specifications, storage conditions and test intervals should all be specified, as should a sampling plan, the data reporting and statistical procedures to be employed, the sign-off and change control procedures to be used, and the proposed expiration dating period for the product.
Batch Selection for Product Registration
Stability studies should be performed on each individual dosage strength and container size of a drug product unless bracketing or matrixing is applied. At least three primary batches of the final formulation manufactured using the same process simulating the final commercial manufacturing process should be tested. These batches should also adhere to the same quality standards and meet the same specifications as the proposed commercial drug product and they should also be contained in the same CCS as proposed for marketing the drug product.
At least two of the three batches should have been manufactured at pilot scale and be based on different batches of the API of the drug. For solid dosage forms, pilot scale is at least one-tenth of full production scale or 100,000 tablets or capsules, whichever is the larger. Other registration studies required to support the registration process include in-use studies, which should be performed on a minimum of two batches, ideally one at the beginning, and one towards the end of the product shelf life; and photostability studies in the proposed drug container system, under either ICH Q1B option 1 or option 2; and a thermocycling or excursion study to support product shipping/transportation and thereby complete the stability study program.
Stability Data at Submission
Based on the data and product understanding, a sponsor should provide: proposed expiration dating period and justification, proposed label storage condition and justification, proposed in-use label storage condition and in-use time period and justification, if applicable.
Stability Commitment
Where long-term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life:
- Submission data from three production batches: continue long term study through proposed shelf-life;
- Submission data from less than three production batches: set more production batches on to make up the three required, using the same protocol;
- Submission data not from production batches: first three production batches to set on stability through proposed shelf-life long term, and for six months in accelerated conditions.
Stability Studies Post Approval
After approval, sponsors are required to undertake stability studies on at least one lot per strength and per packaging configuration under long-term conditions each year as the product is manufactured. These studies are referred to as annual stability or commercial stability, and are conducted to monitor product quality. Sponsors can, through a Prior Approval Supplement, discontinue the annual testing point from standard ICH, and can use the annual stability data to extend product expiry through an annual report. Due to the time lag between product manufacturing and stability initiation, it is recommended to add an expiry test point. It is important to note that commercial stability failure can result in a field alert and/or product recalls.
Additional stability testing (three or six months long-term and accelerated) may be required to support post approval changes in manufacturing process, composition in formulation, immediate packaging and manufacturing of APIs.
Conclusion
Whether conducted in-house by a pharmaceutical company, or outsourced, stability testing is a crucial step in the drug approval process, and assesses how the quality of a drug substance or drug product, and its packaging, will vary over time under the influence of environmental factors such as heat, exposure to light and humidity. The process determines whether any physical, chemical or microbiological changes may affect the efficiency and integrity of the final product, thereby ensuring its safety and efficacy when prescribed. Moreover, stability testing establishes the shelf life and recommended storage conditions of a finished pharmaceutical product and the retest periods for a drug substance.
References
- http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/ Step4/Q1A_R2__Guideline.pdf
- https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/ Step4/Q8_R2_Guideline.pdf
- https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM070273.pdf
- http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/11/ WC500239381.pdf
- https://www.fda.gov/downloads/Drugs/Guidances/ucm070567.pdf
- https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM320590.pdf
- http://apps.who.int/medicinedocs/documents/s19133en/s19133en.pdf
- https://extranet.who.int/prequal/sites/default/files/documents/TRS1010_Annex10.pdf
- https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.166