Clinical trial supplies manufacture

Synthesis of active ingredients Preclinical testing Formulations development Phase I, II, III, and IV clinical trials Clinical trials supplies manufacturing Clinical packaging... 

Category 4 vendors are sole-source API manufactures. First-time clinical trial supply manufacturers, offshore single pivotal trial clinical sites, and... 

Contracting out of activities previously only conducted in-house is already becoming quite common and will probably continue to develop. In the past a so-called full-service pharmaceutical company took direct responsibility for all the activities required for the formulation, manufacture, quality control, and regulatory approval of its drug products. Nowadays the use of specialist contract houses to perform activities such as formulation, analytical methods development, manufacture of clinical trials supplies, supervision of the assembly of an NDA, postmarketing surveillance, and even troubleshooting may be contracted for even by some of the largest companies. 

Apart from manufacturing placebo formulations, the company may need to approach the manufacturer of an already marketed product for clinical trial supplies if their medicine is chosen as a comparator. The precise requirements (such as similar size, colour and no identifying features) can be difficult to meet. Any approach may be met with some hesitation for valid reasons, but equally the reaction may be obstructive, asking for unreasonable access to information. It is customary to provide a copy of the protocol, or at the least an outline of it, with clear indication of the material needed and the timeframe for its supply. 

When the product in question is intended only for use in clinical trials, the fundamental purpose of the regulation, protection of patients from defective products, must still be of primary concern. However, the quantity of product at risk, and its limited distribution will impact the process of complaint investigation. For example, the generally smaller amount of product involved may make it difficult to identify low-level occurrences of manufacturing defects. The limited and more tightly controlled system of distribution of clinical trial supplies, however, will likely facilitate and limit the recall process should that be deemed necessary. 

Aerosol and semisolid dosage forms may be required in some clinical trials. Aerosol manufacturing needs semiautomatic and automatic equipment (Fig. 3) with the capability to produce from 100 to 10,000 units in order to meet clinical supply demands. 

In a perfect world—one with unlimited resources—all validation is performed prospectively three trials are performed and the results are reviewed and approved before commercial use of the process or system. In actuality, there are numerous instances in which concurrent approaches must be adopted, including preparation of clinical supplies, manufacture of orphan and expensive drugs, manufacture of low-volume products, and minor process changes to established products. For reliable processes, there is actually little difference between prospective and concurrent approaches. The results of the validation exercise, whether available from three batches produced over a longer period of time or closely spaced, should be the same if the underlying process is in a state of control (recalling that validation is merely a means of keeping score). 

Failure to comply with cGMP requirements is just one of the areas during clinical trials that may result in compliance issues. Improperly assigned expiration dates, inadequate procedures related to the extension of expiration dates, and abreakdown in any of the steps from manufacture of a clinical trial material to its use in a clinical trial could result in compliance issues. Starting with the manufacture of clinical trial material, there must be well-designed and documented procedures that effectively involve all appropriate persons and departments to assure that only material within specifications is used in clinical trials. There must be procedures that ensure the timely availability of clinical supplies, timely and appropriate extension of expiration dates, timely investigation of out-of-specification (OOS) results and rapid notification of appropriate persons, timely recall of all OOS and expired materials, and timely resupply with fresh materials. Depending on the severity of the compliance issue, the clinical trial could be considered compromised. 

Pharmaceutical products for clinical trials and market supply are manufactured in a multipurpose building. The building is equipped with a flexible HVAC system that allows individual clean room parameter settings for separate rooms. These parameters are set by the employees and documented in a traditional paper logbook Question... 

Clinical supply manufacturing operations are those areas involved in the manufacture of Phase I-IV clinical trial materials, and may include laboratory (or table-top) scale activities, operations performed in a pilot plant (with batch sizes generally larger than lab scale, but smaller than commercial scale), clinical supplies produced in facilities manufacturing commercially approved products, as well as clinical supplies produced at contract manufacturing sitesJ ... 

In practice, FDA only occasionally inspects clinical supply manufacturing sites. However, that should not result in a false sense that an FDA inspection will never take place. Manufacturing sites should always be prepared to undergo FDA inspections. Factors that may cause FDA to inspect clinical supply manufacturers include Review in connection with a preapproval inspection of the commercial manufacturing site routine inspections of contract manufacturers who manufacture only clinical supplies inspections resulting from observed product defects, especially when such defects are linked to adverse reactions in patients (such as contaminated parenterals) in reaction to recalls of clinical supplies or other factors. The FDA inspections of manufacturing operations for clinical supplies used in Phase III trials are more likely than for operations producing Phase I or Phase II clinical trial material. 

Complaints of adverse reactions to clinical supplies are typically seen as reportable events that impact the safety or efficacy of the test article. Companies should give consideration to the possibility that an increase in the frequency or severity of adverse reactions may be linked to a manufacturing defect. For example, a product that has been formulated such that it is super-potent in its final form can be expected to produce adverse reactions of greater severity or frequency than if it was properly formulated. Labeling mix-ups can have devastating impact on patients, or, at minimum, may seriously affect the validity of a clinical trial. Therefore, the following elements should be included in the complaint assessment system ... 

In pharmaceutical research and development (R D), a number of clinical trials are conducted to determine the therapeutic effectiveness of potential new drugs and novel dosage forms of well-established drugs. In order to provide the necessary clinical supplies in a timely manner and to plan for the manufacture of needed supplies, clinical supplies inventory systems are used. 

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