PDA Technical Glossary

A planned set of controls, derived from current product and process understanding, which ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (TR 54) (TR 60) (TR 54-5) (TR56)

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (TR54) (TR54-4) (TR56) (TR54-5) (TR60-2) (TR5 6) (TR 81) An input process parameter that should be controlled within a meaningful operating range to ensure that drug substance critical quality attributes meet their specifications. Although parameters with wide operating ranges may also impact product quality, they are generally easily controlled and not as likely to result in excursions that impact quality and are therefore low risk of occurrence. (TR60-3)

The active ingredient that is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, product-related substances, and product- and process-related impurities. It may also contain excipients, including buffers and other components. [Synonyms: bulk drug substance, bulk material, active pharmaceutical ingredient (API)] (TR14) (TR57) (TR74) (TR60) Active pharmaceutical ingredient in a drug product that is responsible for that product’s therapeutic activity.(TR67) (TR82) (TR88) See Active Pharmaceutical Ingredient (API). (TR56)

Generally used to indicate the following clinical study activities: Microdosing Studies, Phase 1 Trials, Phase 2 Trials, and Phase 3 Trials. See any of the following studies for more information. (TR56)

Studies designed to speed up the development of promising drugs by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. May include the administration of single sub therapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent’s pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body). A microdosing study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. (TR56)

Phase 1 trials are the first stage of testing in human subjects. Often, a small (20-100) group of healthy volunteers will be selected. For life-threatening indications such as oncology, these can be patients that have the target disease but may not yet be the ideal target population. This Phase includes trials designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. (TR56)

Final clinical stage Phase 3 trials are designed to demonstrate the potential advantages of the new therapy over other therapies already on the market; safety and efficacy of the new therapy are studies over a long period of time and many more patients (1,000-3,000) are enrolled into the study with less restrictive eligibility criteria; phase 3 studies are intended to help scientists identify rarer side effects of treatment and prepare for a broader application of the product; phase 3 trials enroll patients to verify efficacy and monitor adverse reactions during longer-term use. (TR56)

An application submitted by a sponsor to the European Medicines Agency (EMA) for approval to market a new drug for human use in Europe. The MAA is similar in purpose to the Biologic License Application (BLA) or New Drug Application (NDA) in the United States. (TR56)

For this report, nonclinical laboratory study means in vivo or in vitro experiments, in which test arti­cles are studied prospectively in test systems under laboratory conditions in order to determine their safety. The definition does not include: studies us­ing human subjects or clinical studies, field trials in animals, or any basic exploratory studies carried out to determine whether a test article has any po­tential utility or to determine physical or chemical characteristics as described in ICH S6 and 21 CFR Part 58 (GLP). Note: Also referred to as Preclinical, Toxicity or “Tox” studies. (TR56)

Studies performed during process development to establish acceptable ranges for key input vari­ables and critical operational parameters that de­fine the process design space. (TR56) A study that evaluates the process to increase process knowledge and examines proposed ranges and their individual and/or combined impact on target protein quality. Process characterization studies include deliberate variation of parameters to determine their effect on product quality attributes, often conducted as small-scale studies. (Also known as process evaluation studies, process justification studies, engineering studies, development studies, robustness studies, or process design studies. (TR60)

The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API (drug substance) meeting its predetermined specifications and quality attributes. (TR14) (TR42) Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. (TR44) The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (TR54) (TR57) (TR74) The collection and evaluation of data, from the pro­cess design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. The documented evidence that the process, op­erated within established parameters, can per­form effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes, as described in EMA, EU GMP, Part 1, Annex 15, drug/me­dicinal product. (TR56) EMA: The documented evidence that the process, op­erated within established parameters, can per­form effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. US FDA: The collection and evaluation of data, from the process design stage through commercial pro­duction, which establishes scientific evidence that a process is capable of consistently deliver­ing quality products. (TR60-2) The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or drug substance meeting its predetermined specifications and quality attributes (1, 17). (TR60-3)

An individual as defined in the European Union pharmaceutical regulation as described in Direc­tive 2001/83/EC that has the legal responsibil­ity for batch release of medicinal products. Note: See also EU GMP Annex 16, Certification by a Qualified Person and Batch Release. (TR56)

The lots of drug substance manufactured to es­tablish the stability profile in support of the regu­latory filing. (TR56)

An appropriately identified reserve sample that is representative of each lot of intermediate product and in each shipment of each active ingredient shall be retained (at least twice the quantity nec­essary for all tests required to determine whether the active ingredient meets its established specifi­cations; this is a regulatory Requirement). (TR56)

Intermediate and final and finished product samples that are stored for the intent of repeating any in-process or release analysis. Typically this is twice the amount of material that is required to perform these. (TR56)

Any food additive, color additive, drug, biologi­cally derived product, etc., for human use or any other article subject to regulation. “Test Article,” in this report’s context, referring to the samples used for toxicity and stability studies. (TR56)

In vivo or in vitro experiments in which test ar­ticles are studied prospectively in test systems un­der laboratory conditions with the primary goals of identifying the following: 1) an initial safe dose and subsequent dose es­calation schemes in humans; 2) potential target organs for toxicity and for the study of whether such toxicity is reversible; and, 3) safety param­eters for clinical monitoring after the appropriate dosing and administering schedule is followed (relevant to the drug being studied). In toxicity studies, the test animals are examined by histo­logical or serological methods in order to iden­tify toxic, mutagenic, or teratogenic effects of the drug. It is sometimes possible to collect physi­ological data from the animals prior to sacrifice. Some toxicity studies may be performed using cell culture methods. Toxicity studies are also de­scribed by the U.S. FDA as “nonclinical labora­tory studies” and by ICH as “preclinical safety evaluations”. The definition does not include studies using human subjects or clinical studies, field trials in animals, or any basic exploratory studies car­ried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics as described in ICH S6 and 21 CFR Part 58 (GLP). (TR56)