Stability testing of pharmaceutical products is a multifaceted set of procedures involving significant cost, time and skillful expertise to build in the quality, safety and efficacies in the drug products. Scientific and commercial success of any pharmaceutical product can only be ensured with the understanding of the drug development process and the countless tasks and milestones that are vital to all-inclusive development plan. The most important steps during the developmental stages include pharmaceutical analysis and stability studies that are required to determine and assure the identity, potency and purity of ingredients, as well as those of the formulated products. Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, protective and informational specifications.
It is considered to be good practice to test the stability of API and Drug products as per International Conference on Harmonization (ICH) Q1A to Q1E or Q5C guidelines. The WHO guideline document QAS/06.179 also provides information on what are the parameters that can be followed for performing the stability studies of pharmaceuticals (both API and Drug product). There are no guidelines (such as those on storage stabilities) for testing to determine the suitability of transport conditions for sensitive products. Although significant amount of literature is available to read and imply on various regulatory authorities and pharmaceutical associations, including USP websites. The Parenteral Drug Associations technical report is certainly the best document to date for planning the testing of products under temperature cycling conditions and evaluating the impact of temperature excursions. The FDA also has presented their views that transport conditions may differ from storage conditions, provided the manufacturer presents satisfactory supporting data.
General testing methods for transport are described by organizations such as International safe Transit Association (ISTA) and American Society for Testing and Materials (ASTM).
A drug product must maintain its identity, strength, quality and purity till its expiration. Physical, chemical and biological data are influenced by various environmental factors such as temperature, humidity and light. In current manufacturing environment, products can be shipped and distributed across different climatic zones. Seasonal changes as well as types of transportation can greatly affect the supply chain of the products.
A major concern of the pharmaceutical industry and health authorities is to guarantee that drugs are delivered to patients without loss of therapeutic properties. An ever-increasing number of therapeutic products developed by the biotechnological or biologics (vaccines) industries require temperature-controlled distribution channels, and it is not infrequent that delays during transport put product quality at risk when transport times and temperature control cannot be maintained. In these cases, the drug may experience “temperature excursions”. Products sensitive to transport conditions need special care to ensure that their quality is not impaired by transport operations. When talking about sensitive products one usually thinks about products that are sensitive to temperature, but other environmental conditions should also be considered, including humidity, light, oxygen, shocks, pressure, vibrations and X-rays encountered during shipment by truck, train, boat, or plane.
In a typical stability program, a stress study is first carried out to determine the drug substance’s degradation path and to establish appropriate analytical methods. Drug substance stability studies are then conducted to define stability under long-term and accelerated storage conditions. In the next phase of the development plan, the drug substance is formulated into a drug product and compatibility of the drug substance with excipients and container parts is then tested. When suitable conditions are determined, long-term and accelerated studies commence with the drug product. The data obtained from these studies are used to define the optimal storage conditions and corresponding retest dates for the drug substance or shelf-lives for drug product.
The stability program will depend largely on the product’s sensitivity to environmental conditions. The product should be understood as the content and the container, both of which determine the final sensitivity. There are three categories in which the pharmaceutical products are classified such as:-
Stable Products: Products not sensitive to environmental changes (e.g., products that are heat sterilized after production). These products will usually be stored at 25°C, and no extensive studies are needed to define the transport conditions. The environment-related considerations should concentrate on finding conditions that preserve the products physical integrity.
Highly Sensitive Products: Products having a limited range of storage and transport conditions. Excursion outside these ranges is an actual cause of product deterioration (e.g., vaccines that deteriorate when frozen).These products need extensive studies to assess the exact parameters in which the products keep their unique properties and those in which they are lost. In addition to tests relating to transport conditions, the testing program should embrace temperature, humidity (if not aqueous solutions), light, oxygen, shock, pressure and vibrations such as those experienced during transport and X-rays if transported by air (cf. airport security systems). They usually cannot be transported outside their long-term storage conditions.
Sensitive Products: Products with a certain sensitivity to environmental conditions and that have to be protected during transport (e.g., most rDNA biotechnology products). These products need the same studies as the Sensitive Products to assess the exact conditions in which they maintain their unique properties and those in which they are degraded.
The pharmaceutical manufacturer can select to transport the products within its storage conditions and should study the effects of transport and possible temperature excursions on the quality of the product until its delivery and use by patients. The manufacturer can also define transport conditions that are less sensitive to failure of transport operations (e.g., room temperature). If so documented, the product can be handled safely outside its long-term storage conditions, provided the manufacturer has satisfactory data supporting the handling/distribution conditions. The degradation of medicaments depends on the value of the environmental conditions and the period of time during which the product is kept at this value. For small deviations from the storage conditions and short periods of time, the consequences are usually not significant.
The temperature excursion study program should start with the determination of global products characteristics, assesses the risks of the distribution channels in relations with product characteristics, establishes the study program and check the results to modify the product transport conditions. The flow diagram as shown below will summarize the steps to build the knowledge of stability program during the transportation study for temperature excursions as per QbD guidelines.
Typically following parameters are chosen for testing during the transportation stability study program / protocol with respective to content and containers:
Y- Test is required, * – Test might be required, NA- Test not required or Not applicable
Tests to assess the consequences of temperature excursions are different in that they are carried out to check the effects of additional stress on the product, such as those resulting from a dramatic situation outside the standard conditions. Preparing them is difficult, since no one knows what will happen in the next deviation situation. Some suggestions are to consider the Mean Kinetic Temperature (MKT) approach and to evaluate the range where the product can keep its properties when stressed by temperature excursions. The MKT is an indirect approach as it gives an evaluation of the temperature supported by the product, which is not a representation of the stress supported by the product; it gives no information allowing the person in charge to evaluate the consequences of the deviation.
If this approach is not practicable, the standard development methods, Design of Experiment (DoE) or “Trial and Error” approach based on the available experience can be used. Some guess studies such as “Temperature Excursions” can help the manufacturer to recognize possible limits and respond to temperature deviations.
It is acceptable to distribute products at conditions outside of long term storage conditions, as long as the transportation conditions are fully tested and that product quality is not compromised. Manufacturers should clearly understand what the consequences of temperature excursions are during products storage and transport from their manufacturing site to customers/patients. The manufacturer must ensure that products delivered to patients comply with the marketing authorization. They should evaluate if the available stability data are sufficient to address the potential temperature excursions. If this is not the case, they should consider starting additional studies to support the release decision in case of temperature excursions, and avoid batches that have adequate therapeutic properties destroyed by insufficient stability knowledge.
Prasad Panzade, Ph.D.
Director Analytical R&D , Product Development Solid dosage