DRUG SAFETY - a major issue in the patient protection worldwide

(PresseBox) (Tuttlingen, ) Globalization has many advantages. Products and services are available around the world, and consumers have a wide range of choices. At the same time, standards have to be harmonized in order to ensure uniform quality and safety parameters. One particularly sensitive area is drug safety. One example of how this works in practice: The DiapharmGroup is an alliance of consulting and service companies who are active in the pharmaceutical and health products industry. The group specializes in drugs and congeneric products such as nutritional supplements, medical products, and cosmetics. The DiapharmGroup portfolio covers the complete lifecycle of products. Designated specialists handle the various aspects, from product concept and development to chemical analysis, preclinical and clinical aspects, regulatory questions, risk analysis, including routine chemical analysis, pharmacological vigilance, and complete lifecycle management. The Zentralinstitut Arzneimittelforschung GmbH [Central Institute for Drug Research] is the service laboratory of the DiapharmGroup and is responsible for quality control of its products. It is certified in accordance with Good Manufacturing Practice (GMP) and is authorized to approve drugs for the market pursuant to the Arzneimittelgesetz [German Drug Law]. Among the main activities of the service laboratory are:

- Method development
- Method validation
- Quality control for drug approval
- Stability testing for certification and/or registration, and
- pharmacovigilance

These activities are designed to ensure drug safety and thus to protect patients. This is quite a challenge in an era of globalization, since drug development and production is no longer performed at one location, but is instead spread around the globe. In addition, markets are now globally diversified rather than confined to a specific continent. In terms of pharmaceutical analytics, the results from research, development, and production must be comparable, reproducible, and verifiable worldwide. Manufacturers must provide documentation for their shelf life data for an extremely wide range of climatic conditions with respect to transportation, storage, and retail conditions. In pharmaceutical analytics, stability tests are performed pursuant to ICH guidelines. These guidelines subject drugs to defined climatic conditions over specific time periods based upon a globally harmonized standard. In these tests, products must undergo little or no change in quality. The aspects initially perceived by patients, namely "organoleptic" factors such as odor, taste and "look and feel," also play a role. This applies to both drugs with chemically defined ingredients as well as vegetable products (e.g. essential oils) and all forms of administration such as solutions, juices, sprays, transdermal systems, cremes, ointments, capsules, and tablets.

The ICH stability tests are performed at the Zentralinstitut Arzneimittelforschung GmbH using KBF series constant climatic test chambers from BINDER GmbH. The ICH tests are a significant component in the process of certifying or registering a product; the characteristic to be documented in this particular case is product stability with respect to a defined climatic condition over a specific time period (shelf life). In addition to the tests for drug certification/registration, "ongoing stability tests" have become increasingly important. These tests are part of the continuous monitoring of drug quality in accordance with Good Manufacturing Practice (GMP). Their purpose is to substantiate that the pharmaceutical product has the stability (quality) appropriate to its indicated shelf life. At the same time, any negative influences on stability, e.g., due to a change of suppliers, should be detected or, even better, prevented from occurring at all. Since 2006, the GMP guideline has stipulated new obligatory specifications for the preparation of product quality reviews and the ongoing stability testing incorporated in them. Consequently, as part of periodic inspection, the regulatory authorities also focus on the special equipment required for stability testing, in this case primarily chambers for constant climatic conditions. Between 5 and 15 product batches are stored in each constant climate test chamber, where they are exposed to defined climates for specific time periods. The climatic data from the test chambers are continuously recorded. In order to keep the climate in the test chambers as constant as possible, door openings are kept to a minimum. It is also important to restore climatic parameters within the chambers to the required levels as quickly as possible after a door has been opened. Although deviations from ICH climate levels can be tolerated, they must be recorded, and the average must not exceed strictly defined narrow limits throughout the duration of the stability tests. BINDER KBF series constant climate test chambers constitute the basis for all of these stability studies, since no ICH-compliant tests can be performed and no GMP-compliant handling of test data is possible without stable test climates. Dr. Sven Oliver Kruse, managing director of the Zentralinstitut Arzneimittelforschung GmbH, who uses BINDER test chambers, considers the following criteria to be particularly important:

- Reliability over the entire lifecycle of the climatic test chamber
- Precision
- Compliance with standards

The test climates pursuant to ICH-Q1A must be maintained reliably and accurately. Stability experiments can extend over a period of three to five years. The climatic chambers must be capable of stable and trouble-free operation during this entire period. Such requirements are no problem for BINDER. Meeting high quality standards has become an integral part of the BINDER corporate culture and its tradition. This is also reflected in the performance expected from the KBF series constant climate test chambers. One of the rules of traceability is that the quality of the test medium must be higher than the quality of the product being tested. BINDER responds to this challenge with its KBF series constant climate test chambers. Like all BINDER products, these chambers also incorporate the full range of BINDER's in-house technologies, such as the "APT.line(TM) " and the "Horizontal Airflow Design." The result is that BINDER can achieve natural conditions for environmental simulation to create optimum preconditions for realistic testing, while complying with all required test parameters, including specified tolerances. The BINDER service team also ensures minimal response times for periodic maintenance calls. This is even more important in the unlikely event of equipment malfunction, when a problem has to be corrected as quickly as possible.

Another important item is compliance with international standards, in this case ICH specifications; this is essential for the results of stability tests to be recognized by the national testing institutions. BINDER covers not only the climatic range required by ICH guidelines, but also a far larger climatic spectrum. Tests can be run humidity-free at temperatures between 0°C to 70°C. Climatic testing with humidity covers a temperature range of 10°C to 70°C, with a relative humidity range of 10% RH to 80% RH. BINDER KBF chambers also maintain constant climatic conditions far more accurately than required under ICH guidelines. The requirements of the GLP/GMP guidelines with respect to recording, processing, and storage of measured data pursuant to FDA CFR 21 Part 11 are equally important. These include, among other things, access rights to current measurements as well as to stored data. The GLP version of BINDER's own APT-COMTM software relieves users of any concerns in this area. The APT-COMTM-GLP software controls and records measured data from up to 30 BINDER units, and meets all of the data security and validation requirements of FDA CFR 21 Part 11. The APT-COMTM-GLP software also provides extensive alarm functions, which can also be transmitted via e-mail or by telephone, including transfer into the mobile telephone network. This range of functions is supplemented with features such as centralized control via TCP/IP, an automatic backup system, and an unlimited number of users.

An optional lighting system in accordance with ICH Q1B, Option 2, is available for the KBF constant climate test chamber. Here, pharmaceutical products are exposed to defined light quantities from defined lighting sources under constant climatic conditions; under ICH-Q1B, Option 2, separate lighting sources are provided for visible and UV light. Users thus have the advantage of evaluating the effect of visible and UV light on the samples either together or separately, as necessary.

As an additional option, BINDER offers customers its proprietary "Light Quantum Control" feature. With this option, lighting intensities can be measured conveniently at the specific sample location and integrated online into the actual light quantity absorbed in each case. Once the specified individual setpoints for visible and UV light are achieved, the lighting sources are switched off individually. The secret: Instead of being planar (like traditional light sensors), BINDER's light sensors are spherical. This allows measurement of light intensity regardless of the angle of incidence. For measurement of the exposure dose, ICH-Q1B guideline prescribes a chemical actinometer, which is an ampoule containing a photosensitive solution that converts the absorbed light quantity at a specific rate. This ampoule is important because it is subject to volumetric expansion, just like a pharmaceutical product. It therefore approximates the photosensitive conditions found in a medicinal drug. The most accurate electronic simulation is spherical measurement with integration using the "Light Quantum Control" option. BINDER is the world's only supplier of this photostability testing process, and holds a patent for this unique feature.

With the KBF, BINDER offers users the following options for stability testing:

- KBF basic model for stability tests pursuant to ICH-Q1A
- Lighting system pursuant to ICH-Q1B, Option 2
- Light Quantum Control option

This is supplemented by a complete after-sales program, and includes the full range of services, such as user-specific IQ/OQ packages and PQ documentation, as well as equipment validation and calibration. Maintenance agreements, a service hotline, and maintenance service are available either from the BINDER service team or from qualified service partners. In short, BINDER provides users with a unique package of products and services for precise, reliable stability testing in full compliance with standards.

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