Clinical supplies manufacturing

Treatment IND inspections (information is available to CDER indicating that an inspection of a clinical supplies manufacturer is warranted to protect the health of patients)... 

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). 

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. 

Finally, incoming components (e.g., raw materials) used to manufacture clinical supplies must be tested for identity using a specific identity test (if available). Specifications should be established and confirmed for each lot of components, drug product containers, and closures received (21 CFR 211.84 and 21 CFR 211.94), and all other provisions of 21 CFR Part 211, Subpart E, Control of Components and Drug Product Containers and Closures not noted in this section also apply to clinical supply manufacturing operations. 

While blending times and tablet press parameters may not be fully established for early phase clinical supply manufacturing of solid oral dosages, those variables have a much lower potential to directly affect product safety than sterility, endotoxin contamination, or objectionable types and levels of particulates do for sterile, parenteral clinical supplies. Because clinical supplies can be incompletely characterized, and are usually given to patients already in weakened conditions, those processes and their related validation data necessary to guarantee patient and product safety (e.g., sterilization and aseptic fill) are expected to be in place as early as Phase I clinical supply manufacture. ... 

Written procedures are required to be established and followed for production and process controls as specified in 21 CFR Part 211.100. Because the specific requirements regarding handling of changes, deviations, and equipment identification are addressed in other sections of this article, and all other provisions of Subpart F are required in order to meet CGMP requirements for clinical supplies, this section will focus on the other aspects of Subpart F that provide unique challenges during clinical supply manufacture. 

Similar logic can be applied to sterilization by filtration or depyrogenation by means of dry heat. In these and other cases, there will be little to no difference in the level of compliance necessary when comparing clinical supply manufacturing to that for the manufacturing for commercially approved products. 

Change control is one of the GMP systems that is applied somewhat differently in clinical supply manufacture than it is in the manufacture of commercial products. Change control does not have a separate and distinct section in the GMP regulations however, the management of change is referenced or mentioned in several GMP sections [see, for example, 21 CFR 211.100(a) and 211.160(a)]. 

In the manufacture of clinical supplies, normally, manufacturing processes are not robust (and therefore not completely validated) until Phase III, sometimes not until the later stages of Phase III. Therefore, the goals of change control in clinical supply manufacture are somewhat different. Those goals should include ... 

When considering OOS investigation procedures for clinical supplies, manufacturers must keep certain basic principles in mind. Those basic principles include ... 

The fundamentals of good data recording practices should be observed in clinical supply manufacturing in exactly the same manner as required for commercial materials. Those fundamentals include the following ... 

Fig. 1 Fluid-bed granulator driers of 1, 5, and 50 kg capacity, which provide flexible clinical supplies manufacturing capacity and can be used to understand critical process variables and scaling parameters.

In order to improve efficiencies within the pilot plant, many firms are abandoning the practice of having separate clinical supplies manufacturing staff and formulation process development staff in favor of a more flexible, responsive group capable of supporting product development from beginning to end. The staff must be trained in formulation development, process... 

Pilot plant processes and manufacturing activities include formulation and process development studies, clinical supply manufacture, and technology evaluation, scale-up, and transfer. Packaging for stability and clinical studies may also occur in the pilot plant, but these activities are often performed in separate, well-defined facilities. It is beyond the scope of this article to discuss all of these areas in detail. Since pilot plant construction is often driven by the strategic necessities defined earlier, only these areas are addressed. 

Efficient clinical supply manufacturing requires a wide range of equipment sizes, preferably of identical... 

Fig. 1 Sterile dosage form processing equipment useful for clinical supply manufacture in the pilot plant. (A) Vial and ampule washer (Metromatic. Oyster Bay, NY). (B) Steam sterilizer (Amsco Finn-Aqua, Apex, NC). (C) Vial filler (TL Systems Corp., Minneapolis). (D)Lyophilizer (Edwards High Vacuum International, Tonawanda, NY). (E) Vial capper (The West Co., Phoenix-ville, PA).

Fig. 3 Aerosol filling equipment useful for clinical supply manufacture in the pilot plant. (A) Manual filling equipment. (B) Automated rotary filling equipment (both D. H. Industries Limited, Barking Essex, UK).

In reality, product and process development and scale-up will be progressing concurrently in order to meet the demands of Phase I and II clinical and long-term safety supplies. The process used for initial clinical supply manufacture will probably be relatively small scale (laboratory scale). As more drug substance becomes available, and the clinical requirements increase, the product batch size will increase to pilot scale, and the process may have to be modified during scale-up. If drug substance is available and very large Phase III studies are anticipated, it may be essential to scale-up to production scale and transfer the process to the commercial production site. 

Assay validation characterizes the assay performance so that the significance of the measured assay values obtained is readily understood [75]. Test methods should be validated when important decisions are to be based on the data generated [30]. Thus, the extent of method validation depends on the stage of clinical supply manufacture. The key elements of assay validation for a method are to establish reliability, the intra- and interlaboratory test variation, and relevance, the meaning of the results for a specific purpose [19]. The robustness of an analytical procedure (according to the ICH-Validation of Analytical Methods, 1993) is its measured capacity to be unaffected by small variations in controlled parameters and reliability under normal usage [35]. 

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