Stability Testing Boosts Drug Quality, Safety, and Efficacy

Drug discovery is slow, inefficient, and risky. It’s also costly—very costly. The median cost of developing a cancer drug, for example, is about (US)$680 million. Worldwide, the cost of developing a single drug exceeds (US)$2.5 billion.

When pharmaceutical companies invest millions in drug discovery, one thing’s certain: They want their products to retain quality, efficacy, and safety once they enter the marketplace. Stability testing ensures that a drug does so by determining both the shelf-life and the quality of a drug.

Shelf-life, says the World Health Organization (WHO), is the “period of time during which a drug product is expected, if stored correctly, to remain within specification as determined by stability studies on a number of batches of the product. Shelf-life is used to establish the expiry date of each batch.”

Benefits of Stability Testing

Stability testing offers several benefits. First, it ensures patient safety. Drug degradation can lead to serious consequences for the patient. For example, the loss of efficacy of a heart medication like a nitroglycerine tablet can lead to a patient’s death.

Second, testing helps manufacturers meet the requirements of national and international regulatory agencies to obtain product approval. Without approval, the drug never reaches the marketplace.

Third, testing protects a brand’s reputation. Testing assures the public that the drug retains its fitness with respect to all functionally relevant attributes as long as the drug is on the market.

Lastly, testing helps manufacturers prepare the registration dossier for regulatory approval by providing support for the dossier’s claims. Post introduction, testing helps verify that no changes were made during manufacturing that might detract from the drug’s performance.

Why Do Stability Testing?

Manufacturers do stability testing for several reasons—all of them critical to a drug’s quality, safety, and efficacy. Testing helps manufacturers:

  • Decide on the best labeling instructions
  • Set a drug or formulation’s re-test period
  • Determine the rate of change in dosage forms
  • Help design better packaging configurations
  • Retention of original properties and characteristics.

In addition, manufacturers also do stability testing on annual production batches once the drug reaches the market to ensure long-term quality over the drug’s lifetime.

Pre-market and Commercial Stability

Stability testing involves developing a protocol designed to evaluate the impact of environmental factors, like light, humidity, and temperature, on the drug. Drug stability includes pre-market and commercial testing.

Pre-market testing occurs during clinical trials, where samples are stored under different conditions and then tested for safety, quality, and efficacy. Commercial stability testing takes place after the drug enters the marketplace.

Some factors that impact a drug’s stability include:

  • Interactions between active ingredients and excipients
  • Drug or product manufacturing processes
  • Type of drug dosage form
  • Container/closure systems used for packaging
  • Light, heat, and moisture conditions during shipment, storage, and handling
  • Degradation reactions like oxidation or hydrolysis
  • Length of time between manufacture and product usage

Companies conduct stability testing in stability chambers, such as Osworld’s pharmaceutical stability chamber, which serves as an important quality attribute for the drug or formulation.

Stability chambers are also called climatic chambers, humidity ovens, and environmental test chambers.

How Stability Chambers Work

Stability chambers provide controlled temperature and humidity environments. They also provide efficient airflow throughout the unit. That ensures that the temperature and humidity inside the chamber always remain consistent.

Stability chambers perform three functions to control environmental conditions within the testing compartment. One function is heating, cooling, and generating humidity.

The other is evenly distributing temperatures and humidity within the compartment. That ensures that all sample parts are subjected to uniform temperature and humidity.

The chamber achieves temperature uniformity using its mechanical system. It consists of a closed-circuit loop containing these components:

  • Compressor
  • Condenser
  • Expansion valve
  • Evaporator

The mechanical system compresses and expands a refrigerant gas to regulate the conditions within its testing compartment. Stability chambers also have safety features, like an additional thermostat, to protect samples and users.

Key features of Osworld’s stability chambers include:

  • Temp. Sensor: PT-100 RTD, Class “A”
  • Humidity Sensor: HUMIREL, Capacitance level, High reliability and long-term stability
  • Temp. Display: Digital LED, 3½ Digit
  • Heating: U-shaped Nichrome wire heater in SS Sheathing
  • Cooling: CFC Free compressor utilizing R134, an eco-friendly refrigerant, with condenser, motor, and relay. Complete Unit – Copeland make.
  • Steam Injection: Boiler with reservoir made of thick stainless steel, with heater, water inlet control, low water level safeguard, and insulation
  • Air circulation: Flange motor with impeller/ blower
  • Chamber illumination: Fluorescent light with door switch
  • Feet: Castor wheels
  • Trays: SS wire mesh, heavy duty
  • Construction: Double-walled with poly urethane (PUF) insulation provided with outer stainless-steel metal door and inner glass viewing door

Stability chambers must qualify at three stages before you can use them for testing: IQ (installation), OQ (operation), and PQ (performance). Metrological or validation personnel use calibrated measuring and testing equipment to evaluate the chambers.

Stability Testing Methods

Stability testing is routine for new drugs or formulations. Depending on the goals and steps followed, stability testing methods fall into one of four categories:

  • Real-time stability testing
  • Accelerated stability testing
  • Retained sample stability testing
  • Cyclic temperature stress testing

With real-time stability testing, manufacturers store three samples at recommended storage conditions and monitor them until the samples fail for whatever reason.

With accelerated stability testing, manufacturers store samples at elevated stress conditions (such as pH, humidity, and temperature) until the samples degrade.

With retained sample stability testing, manufacturers select stability samples for storage for at least a year.

With cyclic temperature stress testing, manufacturers don’t test marketed products. The test is designed based on product knowledge so as to mimic likely conditions in marketplace storage.

Also, regulatory agencies have divided the world into four zones, depending on the environmental conditions the drug is likely to face during storage.

Manufacturers use the conditions in these zones in real-time stability and accelerated stability testing. They’re key factors in the testing.

Since real-time stability studies are time-dependent, manufacturers sometimes do forced degradation studies to assess drug stability over time.

How Brands Do Stability Testing

Manufacturers first must establish a written stability testing program that follows standard operating procedures before testing begins.

The written program includes specific procedures governing the handling of unusual humidity levels or unacceptable variations in temperature distribution. Everyone involved in the drug’s production and testing efforts needs to sign off on the program.

Manufacturers keep test records in Quality Control for a specified length of time. They also conduct performance, maintenance, and verification tests periodically to make sure the testing chamber is operating correctly.

The types of stability testing manufacturers do with the chambers fall into three basic categories:

  • Long-term ambient
  • Accelerated conditions
  • Batch validation testing

Manufacturers test both the drug’s physical and chemical characteristics, which can vary significantly during storage. These changes can impact the drug’s quality, safety, and efficacy dramatically.

How Manufacturers Store Samples in a Chamber

Samples must be stored in containers similar to the packaging of the finished product, just like it would be on the shelf of a pharmacy.

The USFDA recommends that manufacturers store additional samples under stressful conditions for comparison purposes. Samples should come from unopened containers.

Samples are pulled at various periods throughout testing to assess their integrity by doing lab testing and comparing the results against approved stability product specifications.

  • In long-term stability testing, manufacturers store drug samples at a temperature range of 25°C +/- 2°C, with humidity set at 60%RH +/- 5%RH (RH – stands for “Relative Humidity”) for up to five years.
  • In accelerated stability testing, manufacturers store drug samples at a temperature range of 40°C +/- 2°C, with humidity set at 75%RH +/- 5%RH for up to 6 months. These conditions accelerate product degradation.
  • In intermediate stability testing manufacturers store samples at a temperature and humidity range of 30°C +/- 2°C, 65%RH +/- 5%RH. Intermediate testing requires samples to be stored up to 12 months.

Evaluation of Stability Data

Manufacturers use a systematic approach to evaluate stability testing data once it’s collected, using assay methods to turn that data into meaningful, reliable information.

The assay methods used, however, must be specific enough to tell the difference between an unaltered product and the degraded sample. The results usually include data from the physical, chemical, biological, and microbiological testing of samples.

The results may also include data related specifically to the dosage form, the adequacy of mass balance, and the critical quality attributes likely to influence the quality and performance of the drug or product.

Manufacturers can also use regression analysis to evaluating the stability data for a quantitative attribute and establishing a retest period or shelf-life.

Data evaluation is the same for single- versus multi-factor studies and full- versus reduced-design studies. This USFDA paper provides guidelines for evaluating stability testing data.

Stability Testing Protocols

Developing a written protocol describing the key components of the stability test is a pre-requisite for beginning stability testing. The document describes the critical parts of a regulated, well-controlled stability study.

The testing protocol depends on the type of drug substance or product and whether the drug is new or already in the marketplace. A well-designed protocol generally includes the following critical information in a study:

  • Batches
  • Container & closures
  • Orientation for storage containers
  • Sampling time points
  • Test storage conditions
  • Sampling plans
  • Test parameters
  • Test methodology

Also, the protocol should reflect regions where the drug is proposed to be marketed and if the drug is planned to be used in climatic zones I-III, IVa, and IVb.

Role of Agencies in Drug Stability Testing

Regulatory agencies, like WHO, and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), play prominent roles in stability testing activities by issuing guidelines.

Guidelines for drug stability testing originated in the 1980s. These guidelines were made uniform by the ICH and WHO over the years. The guidelines assure uniformity in testing from manufacturer to manufacturer.

National agencies, like the USFDA, also have guidelines for stability testing. They’re based on the ICH’s recommendations. These guidelines outline the frequency and types of conditions manufacturers must conduct on any drug entity to apply for FDA approval for use in the U.S. marketplace.

Maintaining Quality, Safety, and Efficacy

Drug discovery is slow, inefficient, and costly. With companies investing millions in developing new products, the last thing manufacturers want to happen is that a drug loses safety, efficacy, or quality while in the marketplace. Plus, they want to avoid any of the serious consequences that can come with drug degradation.

Stability testing, when done correctly with a validated stability chamber, also known as a climatic chamber, a humidity oven, and an environmental test chamber, ensures that the drug retains these attributes throughout its shelf-life and the drug’s quality is maintained as long as the drug is on the market.

Stability testing safeguards the well-being of patients taking a drug or a formulation. Thanks to the type of testing, patients need not fear that a drug they’re taking has lost its quality, safety, or efficacy.

Osbert Dsouza

Director

Osworld Scientific Equipments Pvt Ltd

www.osworldindia.com

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