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11.7.1 current regulatOry lanDscaPe FOr 3DP Pharmaceuticals
Handbook of 3D Printing in Pharmaceutics
The FDA approval of a 3DP pharmaceutical product (Spritam®) in 2015 is a turning point in the history of 3DP technology in the pharmaceutical eld. Even though all regulatory agencies place a top priority on the quality of pharmaceutical substances to ensure the patients’ safety, no proper guidelines have been issued till now for the pro­duction of 3DP products (Cui et al., 2021). In addition, it is not clear that regulatory permission is required only for the nished product or at all phases of product design, including during manufacture. Even the safety precautions and standard operating procedures are to be considered in the 3DP process because toxic substances may be released at different steps of the 3DP process, like fusion, extrusion, or heating, that affect the skin or respiratory organs (Gioumouxouzis et al., 2019).
11.7.2 gOOD manuFacturing Practices (gmP) in 3D Printing
3DP has shown considerable potential in the pharmaceutical market and has the cap­ability to revolutionize personalized medicine production and drug discovery in the pharmaceutical industry. Various regulatory practices, such as good manufacturing techniques (GMPs), good documentation practices (GDPs), and good laboratory practices (GLPs), are applied to maintain the manufacturing standards of pharmaceut­ical products. Therefore, it is also necessary to develop suitable regulations for the production and marketing of 3DP pharmaceutical formulations, like GMP accredit­ation, which is required for premises that produce and distribute 3DP pharmaceutical formulations (Acosta- Velez, 2016).
11.7.3 Quality assurance anD DOcumentatiOn reQuirements
QbD is an alternative strategy to pharmaceutical product quality assurance that has recently gained popularity. Proper documentation and traceability are also necessary for QC in 3DP to ensure that all manufacturing and QC processes are accurately recorded, managed, and veriable. Recording the materials utilized, the settings of the 3DP process, and the ndings of the inspection are all part of this. By providing this documentation, it is possible to trace the nal product’s origin and ensure its traceability. Document management and storage may require the use of electronic document management.
11.8 CASE STUDIES AND REAL- WORLD APPLICATIONS
Several aspects of a 3DP product, including its mechanical qualities, dimensional accuracy, surface quality, and compliance with specications are considered and assessed to establish the quality of the product by NDTs. It was reported that the NIRS was employed for in- line process control of different layers of UV- curable printing inks (Mirschel et al., 2014), evaluation of 3DP pharmaceuticals (lms and tablets), and near- infrared chemical imaging to study inkjet- printed pharmaceuticals (Vakili et al., 2015). Raman confocal spectroscopy nds its use in examining the
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FIGURE 11.2 Determining the dosage content in polyprintlets using a portable NIR device.
(Treneld et al., 2020.)
distribution of the medication and polymer within the 3DP tablet. In situ sensors and cameras are used to acquire process data for quality analysis and real- time monitoring of the 3DP techniques. A thermal camera is utilized to collect facts regarding the potential degradation processes (Aho et al., 2019), which aids in chemical mapping of the drug and excipients and also to observe the variations in the solid forms of the nished product.
According to Figure 11.2, a study was carried out to determine the dose content of the polyprintlets containing two different medications (lisinopril and amlodipine) placed into cylindrical polyprintlets and 3D- printed lms, with drug concentration ranges from 1– 20% w/ w and 1– 3% w/ w, respectively, by a portable NIR spectrom­eter non- destructively, and calibration models were also established (Treneld et al.,
2020) and compared with HPLC output.
A quality management system, “certify- as- you- build”, can watch a printlet throughout the printing process and identify print aws in real time by comparing the created geometry with the computational model and 3D- DIC can be used to capture the structure and record the real- time aws in 3DP product (Holzmond and Li, 2017). Figure 11.3 represents the real- time fault detection of specic and general defects by 3D- DIC.
11.8.1 exemPlary Qc strategies in 3DP Drug FOrmulatiOns
Non- destructive testing is frequently used to provide efcient QC and preventive or predictive maintenance without altering the properties or original state of the material. One of the main purposes of the adaptation of QbD and PAT is to facilitate real- time release testing (RTRT), ensuring the quality of the medicinal product without dam­aging end- products. Taguchi’s strategy is to complement approaches to conventional experimental design methods because it combines engineering and management approaches with statistical ones to produce improved- quality products and reduce costs quickly.
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Handbook of 3D Printing in Pharmaceutics
FIGURE 11.3 Real- time fault detection of both specic and general defects by using 3D­DIC. (Holzmond, et al., 2017.)
11.8.2 lessOns learneD FrOm successFul imPlementatiOn
OF Qc methODs
Several factors, such as production process, the material being used, and the exist­ence of contaminants, inuence the selection and application of a non- destructive testing technique as each approach has its own guiding principles. Even the regula­tory measures need to place a lot of emphasis on the quality assurance and manage­ment steps that lead to product formation by using new approaches to ensure quality throughout the production process.
11.8.3 Future trenDs anD aDVancements in Qc FOr Pharmaceutical
3D Printing
3DP is a breakthrough innovation; it provides novel approaches for both patients and the pharmaceutical industry that have a signicant impact on the pharmaceutical sector. The QC methods that are employed for traditional pharmaceutical products are not suitable for 3DP products so NDTs are adopted for the characterization of 3DP pharmaceuticals. Spectroscopic techniques like NIRS, Fourier transform NIRS, HSI coupled with NIRS and RS, or Raman confocal microscopy can be installed ofine, at- line, or in- line, and they can yield both quantitative and qualitative data. Another method, using an advanced algorithm, has been developed by ZoomlabTM (Tracy et al., 2023), which helps to select the optimal excipients for a given API. This method minimizes costs by reducing the requirement for several laboratory tests, reducing wastage of expensive excipients, and checking the compatibility of various excipient– API combinations virtually. The numerous technological and legal challenges and the availability of online non- destructive quality- control procedures that 3D printing technology is currently confronting will be resolved in the near future.
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11.9 CONCLUSION
207
3DP has received signicant attention from the pharmaceutical industry over the past ten years owing to its rapid production, affordable price, and versatility in pharmaceut­ical formulations, thus enabling patients to obtain more effective and safer medication. In the pharmaceutical sector, quality control is a fundamental and crucial activity that ensures high- quality pharmaceutical products. The primary objective is to ensure that the product is safe, efcient, consistent, and reproducible throughout the entire manu­facturing procedure. So it is critical to improve 3D printing quality since low standards could discourage consumers from buying 3D- printed products. Conventional QC techniques that have become prevalent in large- scale manufacturing represent the end­product testing paradigm; such approaches are generally destructive and inappropriate for the 3DP. This demands the development of a non- destructive PAT that requires little to no sample preparation and retains the integrity of the nished product. PAT is currently gaining recognition in research as a QC technique that allows the monitoring of the production process by offering real- time evaluation and management of critical process parameters and previously established CQA. Non- destructive techniques like 3D- DIC, photogrammetry techniques, NIR, RS, and hyper imaging are employed to reduce manufacturing oversights, material waste, variations, and imperfections in the 3DP process, as well as to enhance product quality during the manufacturing process. QC techniques and regulatory strategies like GMP at every stage of manufacture are crucial in enhancing the quality of 3DP formulations.
ACKNOWLEDGEMENTS
The authors are thankful to the management of Malla Reddy Pharmacy College for their unwavering support.
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3D- Printed
12
Pharmaceuticals
Current Regulatory Scenario
Raja Rajeswari Kamisetti, Ajmeer Ramkishan, Prakash Katakam, and Subhas Sahoo
12.1 INTRODUCTION
3D printing (3DP), an expository advancing technology in versatile fabrication systems including pharmaceuticals, bio- medicine, aviation and automobiles and so on with its ubiquitous utilization with an expectation to grow signicantly to $42.9 billion by 2025 (CAGR Markets press release, Tracy et al., 2023). However, despite its potential and focus on digital savings, there is no systematic plan for 3DP. While compliance with rules is generally lacking in nations like India, certain countries have specic regulations focused on certain areas such as medical equipment.
These innovations are contemporary with multiple edges to the pharmaceutical industry, during early stages of drug development by their less time and expend­iture. The timelines in the developmental stages was marked during the COVID- 19 pandemic requiring rapid drug development and repurposing trials. In the course of pre- clinical and clinical formulation development, this technology is a prototype tool to rapidly evaluate intermittent batches of dissimilar drug product replications with a jolt on critical quality imputes.
3DP is a viable alternative to traditional manufacturing processes in the pharma­ceutical business for producing personalized medications, offering cost savings compared to conventional procedures. However, these formulas have signicance in improving medicinal effects. Formulations can be customized to individual patient requirements using 3DP under controlled conditions, a procedure already employed in the healthcare sector. Many manufacturers use this technology for the mass pro­duction of personalized hearing aids.
Industries worldwide must proactively adjust and shape the direction of tech­nology, while governments should prioritize 3DP. In recent times, major nations such as China, the United States (US), and the European Union (EU). China has been actively developing its 3DP business and implementing policies to regulate these technologies. In 2017, an action plan called the “Additive Manufacturing Industry Development Action Plan (2017– 2020)” was created (www.gov.cn/ xin wen/ 2017- 12/ 14/ cont ent_ 5246 754.htm).
211DOI: 10.1201/9781003439509-19
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In 2018, “Centre of Medical Devices Evolution” of China issued suggestions for the management and directive of 3DP medical equipment that are specically custom­built additive- manufactured medical devices (www.cmde.org.cn/ CL0 063/ 6954. html). In 2020, technical guidelines were adhered to permit the production of 3DP replacement vertebrae www.cmde.org.cn/ CL0 112/ 21043.html) and an acetabular cup (www. cmde.org.cn/ CL0 112/ 21042.html).
In 2017, the Federal government made a signicant shift when the Foods and Drugs Administration of USA (FDA) issued recommendations aimed at additive produced medical devices (Martin et al., 2017). The agency authorized the produc­tion of 3D- printed parts for commercial engines (www.ge.com/ news/ repo rts/ the- faa­clea red- the- rst- 3d- prin ted- part- to- y- 2).
The Federal government has attempted to regulate the misuse of 3DP of rearms by introducing multiple laws in Congress (H.R.7115 2015). Despite being obscured by darkness, regulatory rules have been developed based on important recommendations.
12.1.1 key regulatOry cOnsiDeratiOns FOr 3DP Pharmaceuticals
Design and development: the design and development of 3D- printed pharmaceuticals must be carefully controlled to ensure the safety and efcacy with regard to the products. This includes material choices and design of the dosage form, and the printing process.
Manufacturing: the manufacturing of 3DP pharmaceuticals must be done in con­formity with good manufacturing processes (GMP). This ensures that the products are produced consistently and reliably, and that they meet the required quality standards.
Quality control: 3DP pharmaceuticals must be subject to rigorous quality- control testing to ensure their safety and efcacy. This testing should include the tests to determine the identication, pureness, strength, effectiveness, and stability of the pharmaceuticals.
Labeling: the labeling of 3DP pharmaceuticals must be accurate and complete, and it must comply with all applicable regulations. The labeling should include informa­tion about the ingredients, the dosage, the route of administration, and the storage conditions.
The regulatory landscape for 3DP pharmaceuticals is still sprouting, but it is apparent that these products will be subject to austere regulations to warrant the safety and efcacy of these products, which have the potential to revolutionize the way to deliver medicines.
12.2 US FOOD & DRUG ADMINISTRATION (USFDA)
The regulating body is responsible for ensuring the safety and efcacy for the med­ical supplies such as medicines, biological products, and medical- devices, including 3D- printed medical products. The USFDA does not have strict monitoring in place
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for 3D printers, but it does closely oversee the automated processes and production of these 3D printers if the resulting product are medical devices that meet quality standards.
3DP devices must adhere to regulatory regulations, like all other devices. Premarket requirements relate to medical devices before they are launched, whereas post- market essentials use on medical products after they are sold.
There are three groups of medical equipment: Class I, Class II, and Class III. As you move from Class I to Class III, regulatory control grows.
The futuristic 3D printing technology and FDA’s policy relates to the following:
(a) the fabrication, labeling, marketing, manufacturing, and analysis of regulated products, (b) the dispensation, at ease, for assessment or endorsement of regulatory submissions and (c) scrutiny and implementation of guidelines.
But the authority also states that a substitutional determine if it meets the criteria of the relevant laws. Hence, this outlined guidance is predominantly organized into two specic sections:
12.2.1 Design anD manuFacturing cOnsiDeratiOns
This involves addressing technical factors to comply with Quality Systems (QS) standards for a device based on its governing category or applicable legislation. The guidelines cover manufacturing issues and thoroughly address all regulatory criteria needed to develop a quality system for device manufacturing (U.S. Food and Drug administration, 2017).
12.2.2 DeVice testing cOntemPlatiOns
The section 510(k) of the guidance describes how to submit premarket notica­tion submissions, related to applications of premarket approval (PMA), humani­tarian device exemption (HDE), investigational device exemption (IDE) and de novo requests for 3D- printed devices.
The device categorization system denes the statutory prerequisites for general device types. Mostly devices belonging to Class I are exempted from section 510 (k), however the rules are mandatory for the devices belonging to Class II and Class III devices (www.gov.cn/ xin wen/ 2017- 12/ 14/ cont ent_ 5246 754.htm).
Based on their inventiveness, 3DP has versatile medical applications, medical devices are regulated by the Center for Devices & Radiological Health (CDRH). The Center for Biologics Evaluation and Research (CBER) regulates biologics and the drugs are regulated by the Center for Drug Evaluation and Research (CDER).
Whilst the general 3DP devices are controlled by CDRH, the CBER oversees the regulatory oversight of all applications of additive manufacturing that use biological, cellular, or tissue- based materials. The CDER oversees medication applications involving 3DP, while the Ofce of the Combination Products (OCP) supervises goods with components typically overseen by multiple FDA Centres.
The FDA has not yet established a denitive policy regarding 3D- printed pharmaceuticals, but it has afrmed that they would be regulated as drugs or med­ical devices, depending on the specic product. The Foods, Drugs, and Cosmetics