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34 Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 P h a r mTe c h . c o m Manufacturing ment stage, adequate toxicity information could be lacking, and therefore it is common to use default classifications (both potent and toxic) to ensure worker safety during manufacturing. Matching the compound to the micronization capabilities, and securing appropriate containment equipment, are the next steps of program onboarding. A materials categorization group, perhaps sup- ported by expert opinion, reviews API data to decide whether a company's facilities and equip- ment are capable of undertaking the manufactur- ing process. Typically, the information required at this stage includes matching the API characteris- tics to facility capabilities; identifying the needs for equipment containment and the equipment scale re- quired; specifying the cleaning of multi-use equip- ment; the desired yield; and whatever containment monitoring may be necessary. Other information to be considered may cover restricted drug classes, controlled drugs, and environmental issues. Once the material categorization has been assessed alongside the necessary control measures, options can range from processing of non-potent APIs in an open bay, the use of flexible containers, or processing in hard-wall isolators for HPAPIs. The priority is to ensure operator safety and hav- ing the appropriate containment measures and equip- ment cleaning processes in place to reduce risk of ex- posure. Investment in equipment, operator training in current good manufacturing practices, process safety, and cleaning procedures are paramount. The development phase of a drug will inf luence what data should be available; and a more conser- vative approach may be required if data are miss- ing. For a drug at a very early development stage, clues to its potency may need to be taken from the targeted therapeutic area, alongside structural f lags in the molecule and comparator molecules. For preclinical programs, in-vitro genotoxicity data may be available, as well as information on the mechanism of action and cytotoxicity. Through the clinical phases, information on animal stud- ies, expected dosage levels and human data will be generated, and as the data package increases with information, assessment on necessary handling and containment may need re-evaluating. When working with full commercial products, a full data package is required as a safety data sheet (SDS) is unlikely to be enough, and a permitted daily exposure (PDE) limit or an occupational ex- posure band (OEB)/occupational exposure limit (OEL) report from a toxicologist is important. Onion skin approach The onion skin model (Figure 1) illustrates a design philosophy that allows containment activities to be built out from a core to ensure all controls and measures are in place for effective handling and operator safety. At the center is "control at source," which involves the appropriate equipment to be installed within a facility to carry out the micronization, at the ap- propriate scale, and with the correct seals to handle potentially hazardous materials. Beyond that are the engineering controls that cover the contain- ment and isolation requirements. The third layer is the transfer ports and interface into the isolators, which are crucial to ensure containment integrity. The final, "physical" layer is the design of the facility, with its extraction system, and access controls for staff into the area handling the materials. Above the physical installation are the processes that dictate the safe handling, the establishment of standard operating procedures and paperwork,