By Joachim Leube, Bayer HealthCare Manufacturing, Italy
New options of therapy are needed for a considerable number of diseases. Nowadays research in this field has extended from classical big pharmaceutical industries to a large number of smaller, often just recently founded organisations, which have a huge innovation potential, but also a need for clear guidance of how to move a compound from the research laboratory to approval for commercial use. This need is enhanced by the recent changes in the regulatory environment, one example being the FDA guidance on GMPs for phase I, which actually has been found confusing by a large number of experts in the field.
PDA is currently in an advanced stage of editing a technical report (TR) on GMP points to consider for investigational drug products. This report will cover the whole spectrum of clinical development from phase I through phase III, encompassing both chemical and biological therapeutic agents administered as finished drug products. Looking from a different angle, it covers all aspects from starting materials and production through testing and batch certification and release up to and including distribution and the associated logistics of getting a safe, and hopefully effective, finished product to the patient participating in the clinical trial. The report adopts an incremental approach to application of the GMPs in manufacture of investigational drug product while advocating an appropriate quality system at all phases of human clinical studies.
The TR starts by introducing the reader to the regulatory environment, highlighting the differences in regulations and expectations in the different regions.
Everyone participating in a clinical trial has the right of maximum protection against avoidable risks, including those arising from lack of quality of the investigational drug. The TR shows how to set up a state-of-the-art quality management system and how this helps in achieving the ultimate aim of product quality. The main elements of such a quality management system are explained, including systems for the management of documentation, changes, deviations, training and audits, among others. Included is also a differentiation or an incremental approach to the system as the investigational drug product moves from manufacture of early phase (1 / 2a) to late phase (2b / 3) trials. This approach is continued in subsequent chapters which address specific areas of GMPs always considering where a simplified model might be used for early phases and subsequently enhanced as necessary as production and controls move to later phase manufacture and knowledge of process and product increases.
In the area of materials management the reader will find information on control over the supply chain, supplier qualification, and other relevant topics to ensure that the components and raw materials used for the investigational drug product are of the appropriate quality from arrival through their use in production up to and including the shelf life (expiry / retest or use by date) of the finished investigational drug product.
The manufacture of investigational drug product is often challenging because of the limited knowledge of the toxicity, potency and / or sensitising potential of the active substance. The TR includes points to consider in the design and qualification of facilities, equipment and production processes used in the manufacture of investigational drug product, considering the important aspects of avoiding cross contamination or mix-ups, containment, cleanability and change-over procedures between campaigns, while maintaining the necessary flexibility in the process and nevertheless ensuring that the manufacturing process is in a state of control. Both oral and parenteral drug products are covered, with the specific requirements for different types of dosage form considered.
A chapter on quality control and laboratories addresses topics such as sampling, method development, qualification and validation, as well as specification setting, expiry dating and stability testing requirements.
Packaging and labelling are particularly critical for investigational drug products due to the need for randomisation and blinding for certain studies. The large variety of set-ups possible to flexibly adapt the packaging and labelling to the different clinical studies has been considered in this chapter.
Investigational drug product manufacturing and controls are reviewed as part of the certification and subsequent release (or rejection) of each batch, and the TR describes the pre-requisites for performing these tasks, as well as the options for extending shelf life, where applicable.
Last but not least the topic of distribution and how to ensure adequate control over the investigational drug product through delivery to the clinical trial site is explained, including modern, electronic approaches to distribution control.
The TR concludes with a section on references to the current guidelines and rules governing the manufacture, quality control and certification and release and distribution of investigational drug products.