Pharmaceutical stability is defined as the ability of the product to maintain its chemical, physical, microbiological and biopharmaceutical properties within the specified limits throughout its shelf life and under the proposed conditions of use.
When a drug does not have adequate stability, it can expose the patient to risks associated with the reduction of the therapeutic effect or the manifestation of adverse events and toxicity caused by the formation of degradation products.
Drug stability studies should assess several aspects to identify which factors most influence the change in product characteristics.
Therefore, extrinsic factors such as temperature, humidity or light must be evaluated; and intrinsic such as physical-chemical properties of the active pharmaceutical ingredient, excipients, pharmaceutical form, manufacturing process, type and properties of packaging materials.
The main objective is to demonstrate stability in all aspects important to the API and the drug:
· Chemical: maintenance of declared integrity, content, and purity within specified limits for a given period.
· Physical: maintenance of organoleptic and physical properties including appearance, taste, odor, pH, viscosity, hardness, among others.
· Microbiological: refers to sterility or resistance to the growth of microorganisms, which must remain within the specified limits.
· Pharmacological: related to the maintenance of therapeutic efficacy.
· Toxicological: addresses a possible decomposition process, both active ingredient and of the excipients of the pharmaceutical preparation, capable of originating products that have some level of toxicity.
There are several different types of stability studies:
Forced Degradation Study: allows the generation of degradation products through exposure to stress conditions and aims to develop methods indicating stability and provide information about the possible degradation routes of a given product;
Photostability study: aims to assess whether the API or the drug remains within specifications when exposed to light. If the product does not remain stable, the company must protect the product from exposure to light with suitable packaging material and adopting protective measures in the manufacturing process, storage and use of the product.
Accelerated stability study: designed to accelerate the chemical degradation and/or physical changes of a pharmaceutical product under forced storage conditions, aiming to assist in the determination of the shelf life or retest and evaluate the impact of short exposures to conditions outside those established;
Long-term stability study: designed to evaluate the physical, chemical and microbiological characteristics of an API or drug, under the proposed Storage Conditions and Shelf Life. The test must be performed every three months in the first year, every six months in the second year, and once a year during the period to be evaluated;
In-use stability study: a study designed for drugs packaged in Multidose Packs to provide information that proves the period of use for which the drug maintains its stability, after opening, and subsequent reopening of the Primary Packaging under the conditions determined by the period of use;
Post-reconstitution or dilution stability study for drugs: mandatory study for drugs that need dilution, to demonstrate for how long the product remains within specification after preparation. It must be performed at the start and end times of the Long-Term Stability Study and with all solvents indicated in the package insert.
Follow-up stability study: aims to monitor and confirm the Shelf Life for the drug and the API Retest Period after the start of marketing, evaluating whether the product maintains the characteristics according to the results obtained in the long-term stability studies. At least one batch per year must be included and monitoring is carried out every 12 months until the expiration date;
No single study is able to prove the stability of the product, it is the set of data that can indicate the best composition, production process, type of packaging, storage and use conditions that guarantee safety and effectiveness until the end of the shelf life.
Collegiate Board Resolution (RDC) No. 318/2019 establishes criteria for carrying out stability studies of active pharmaceutical ingredients (APIs) and synthetic drugs. For products, RDC 412/2020 must be applied.
Sources:
• Meirelles, L.M.A - Drug stability: State of the Art. Electronic Journal of Pharmacy - http://revista.oswaldocruz.br/content/pdf/edicao_7_jessica_mirco.pdf
• Souza, J. – Stability study: Factors that influence drug stability - https://www.arca.fiocruz.br/bitstream/icict/11826/2/Julianenielydesouza.pdf.
• RDC 318/2019 - Establishes the criteria for carrying out Stability Studies of active pharmaceutical ingredients and medicines, except biological ones, and makes other provisions.