encapsulating liquid products: trends and innovative solutions.
[ Slightly] Illustrations Production of liquid- Filling capsules has become a very good solution for the pharmaceutical industry. With a variety of developments and innovations, liquid filling technology is increasingly considered hard-Capsule filling. This trend of providing users with various filling process solutions stems from the variable properties of products on the market. To this end, the high-performance filling machine for liquid packaging has been at the forefront, providing a more flexible and cost-effective Robert Bosch\'s Felix Nink explains the pharmaceutical aspect of liquid filling, until recently, liquid- Filling capsules as a clinical trial or newly approved preparation is not the first choice; This is due to various sealing or handling problems encountered in the past. Different from standard powder capsules, liquid capsules The filled capsule shell is in close contact with the active substance, so there is a risk of increased material migration or distribution. However, the packaging technology has been improved and developed over time, and users have seen the benefits of formulating liquids and semi-liquids Some of the applied solid fillers are in hard gelatin capsules. Drug active substances with low melting point, low dose and critical stability are difficult to develop in solid oral dosage forms; Therefore, as a preparation for liquid or asemi- Solid filling of gelatin capsules has proved to be a better choice. A substance with a low melting point may liquide or become \"sticky\" at room temperature \". Therefore, in order to maintain the flow properties that allow processing and filling, a large number (up to 50%) Excipients must be added. In the case of high doses, this may cause the volume to no longer be suitable as a preparation for a single dosage form. Since the heat generated by compression causes the material to melt, the low melting point also affects the compression process in the production of tablets. To this end, the manufacturer has turned to filling hard gelatin capsules or soft gelatin capsules with liquid preparations. Drugs used at a minimum dose are not easy to produce solid oral form. Because the drug is highly powerful ( Toxic drugs, hormones, etc) The risk of cross-cutting has increased Pollution and harmful dust that employees may be exposed to during production. For industrial production, as well as hospitals and community pharmacies, dust- Free liquid or half Solid preparations are an effective alternative to preventing these risks. In low- Small differences in the density of dose drugs, powder mixtures, or changes in the uniformity of mixtures may produce unacceptable levels of content uniformity. This change can be avoided with liquid or semi-liquidsolid drugs. Another group that benefits from liquidation or semi-liquidation A solid preparation is a substance that is unstable when exposed to oxygen, light, or humidity. Although there is a certain amount of air in the capsule, the hard gel capsule provides a reliable defense against oxidation due to the production process. Sealing Liquid- A significant disadvantage of filling capsule hard gelatin capsules is that they tend to leak at the joints between the body and the cap. Until recently, the binding process- Gelatin film with overlapping cap and body area-- Is the only way to solve this problem. Novel questions ( Liquid package via micro spray)process-- Where, spray a solution of ethanol and water between the overlap of the body and the hat- The market has been introduced to simplify the closure of hard gelatin capsules. LEMS technology provides automated capsule filling and sealing for the preparation of early clinical trial supplies without binding. This new technology utilizes the low surface tension of ethanol/aqueous solution, allowing the solution to quickly penetrate into the overlap between the body and the membrane. The ethanol/water mixture slightly dissolves the gelatin between the membrane and the body, dissolved during gentle heating (40-60[degrees] Less than a minute) Complete the fusion of two gelatin layers. Technology like this speeds up the time frame for drug development, enabling people to get \"human first\" more quickly, one of the most compelling arguments for filling liquids or semi-liquids Solid in the capsule The development time of liquid capsules is shorter than that of powder tablets, so it is suitable for early clinical trials. Even small industrial filling and sealing machinesscale filling ( About 20- Formula 50g) Efficient compounds can also be accommodated. Closure and bundling provide closed capsules with a low scrap rate in terms of quality control, which greatly reduces the cost of clinical trials. Nevertheless, there are still some drugs on the market that have been economically successful in the past few years, but have not yet been replaced by other preparations. Table 1 provides a brief overview of the drugs currently provided in hard gelatin capsules. The problem that the ROI of liquid filling often occurs in the early stages of the formula is liquid- Filling capsules are compared at cost with other oral dosage forms such as powder capsules, tablets and granulesCapsule. Of course, the cost composition includes development and raw materials; Taking into account the development and manufacture, because there is no need for complex equipment, liquid- The requirements of filling capsules for environment and GMP are greatly reduced ( Production Practice) Compliance requirements for drugs that are more effective than standard capsule or tablet formats or are toxic. This has a significant impact on reducing the cost of special rooms, buildings and air treatment, as well as simplifying the handling procedures. Scale- As the filling/sealing process is achieved on equipment of the same size, the cost is reduced relative to the batch size of 3 000 capsules per hour. In addition, another argument for liquid filling is that without excipients, it is almost impossible to compress the active ingredients into tablets. However, the packaging of pure drugs is possible due to the development of filling technology; It also provides the opportunity to fill incompatible active ingredients without any loss of potency. Low melting point active substances are sometimes needed during development. For this purpose, products such as PEG 10 000, colloidal silica or polyethylene polypropylene ethylene glycol polymer are used and used for products such as Permixon 160 mg and Piasclodine 300 mg. In addition, liquid The filling capsule provides controlled release based on pro-fat or two pro-sex ingredients such as egg yolk, beeswax, monogamate, soy or palm oil. Usually, biological utilization is better than when powder and liquid are used In general, the filling capsule is more compatible with other preparations in terms of moisture absorption, mechanical resistance and dissolution. A big advantage is the opportunity to make rules. Emulsion system to improve the water-soluble of refractory APIs ( Such as pro-fat components or low HLB surface active substances). A coarse emulsion is produced when diluted, but these do not precipitate active ingredients over time. Last but not least, liquid capsule filling is very flexible. Liquid can be filled separately or with tablets, particles, solids Capsules filled with liquid are usually also in line with a clean \"inside \"GMP operations and costs-effective. Some of the disadvantages of liquid filling are that there is a significant contact between the formula and the shell, and an increase in the water content of the shell will cause effects such as zoning, swelling of the capsule or shrinking of the cap. Capsplitting can happen, which is usually followed by an active migration. Physical stability is sometimes critical due to oversaturation, polymorphism, and chemical degradation. The most serious problem is the weakness of filling the capsule during the bone removal process. In order to make this technology feasible, there is a need for promising development in the field of blister design in the near future. PAT, liquid-filled capsule of the American Food and Drug Association (FDA) The \"process analysis technology\" initiative launched in 2002 called for adequate understanding and control of the pharmaceutical production process. Liquid- Filled hard gelatin capsules require a rigorous review of several aspects: for example, developers, production qualified personnel, quality assurance and quality control. Among the different manufacturers, BoschPharma Liquid provides a range of devices that can effectively Online analysis and control of key process parameters for filling liquid drugs. The company works with multiple customers to integrate PAT technology into filling and production lines. At several points in the capsule filling process, the quality parameters are monitored and controlled, and at the same time, the capsules with unqualified quality are identified and eliminated during the preliminary sorting process. Not only found the problem; They are fixed one way in the closed loop and identify the fault before the fault seriously affects the downtime. The production of high quality liquid filling capsules needs to meet some of the necessary standards such as risk and data management, filling process, PAT and quality aspects. * The first step should be the risk assessment of processes and equipment. The key quality attributes must be determined and then the filling machine and process are properly designed. In order to solve complex control tasks, innovative analyzers or sensors are often required. Deep market knowledge of analytical process monitoring equipment helps to find suitable sensors for expected measurement tasks; * Secondly, users should plan their IT structure data management verification during the design phase of the production equipment. Before specifying the start of writing, questions need to be answered about the amount of data that will be stored, calculated and used for automation and control; What kind of data will it be ( Digital/serial, original data format, uni/multivariate in storage format) What data supports the requirements of 21 CFR Part 11? * Also, the user needs to know how to process the raw data, what is availability, can the data be audited, when will the statistical tools, methods, or online forecasting software be needed? They need to make sure that the data management system can be validated, whether it is- The process control of secure data transmission is available or necessary, and whether the data is in-Online and online. Regardless of the filling process and equipment, the quality of the design usually depends on how the process is run. Proper machine design should be able to implement the customer\'s quality control strategy without losing information in the daily manufacturing process. * The last step is to develop powerful manufacturing processes that are monitored by smart sensors under regular conditions and often evaluated through statistical calculations, and by trained personnel (such as dealing with qualified quality and regulatory issues of production. Today, the machine supplier is very open, not only to make the right machine, but also to provide technical solutions for each filling process. Last but not least, the whole purpose of PAT is to guarantee the unit-to-unitquality. If the pharmaceutical industry is able to provide the same level for a product over a long period of time, PAT is effectively implemented. [ Slightly] Illustrations\"Unit-to- \"Not just\" batchto- Batch, \"regular\" single dose to single dose unit. For packaging as well as other pharmaceutical processes, patients will never accept drugs produced under \"irregular\" conditions. Take a look at the \"approved\" quality control rules in the official pharmacopoeia and sampling is allowed on a very small statistical basis. This is basically essential; If only 30 capsules are analyzed by qc and considered as \"representative\" of the entire batch, then the analysis results cannot be traced back to the process when filling a single capsule. For example, the sampling and acceptance strategy is to check a random sample of 30 units and, if not, accept the batch Units found to meet ( Zero tolerance standard). The possibility of passing a maximum of 7 batches is about 10%. 5% non- In line with the unit, and the probability of failure in a batch containing only 0 is slightly higher than 10%. 4% non- Meet the unit. If only 30 samples are analyzed, these observations do not guarantee the quality of the unit that has not been tested. In contrast, no non- The qualified unit in the test sample does not necessarily mean that there is no non- Meet the unit. Therefore, even if the zero tolerance standard is an element of the final product test, it cannot completely eliminate the non- In line with drugs! 100% in-is a better solution Production line control for manufacturing process. Liquid Filling of capsules must comply with gmp- As regulated as other processes. The PAT tool helps to control the process parameters and key attributes in regular production in a sucha manner, and the finished capsule always meets the specified quality. The strong trend of innovative technology solutions to fill capsules with liquid products is not only identifiable in the health care products market, but also in the pharmaceutical industry. More and more different products put forward higher and higher requirements for this technology. . . Drive equipment suppliers to seek innovative technology solutions. Especially in the last two years, the technical equipment used to process the clearing products- Partly due to some very special filling properties- Obviously. As mentioned earlier, liquid filling technology has proven to be safer and easier to handle, especially when dealing with highly toxic products. Some key properties of variable filling liquids that affect the filling process include product viscosity, product melting point, product composition, and thread formation (tailing). Plus these, the tendency of the degassing behavior to react with other media (such as oxygen) The act of separation (segregation) And/or wear forms a complex matrix of parameters that can influence the filling process decisively. To this end, a system that is product-specific and flexible is required. Friendly and efficient. Today, broadband wide products with high flexibility show a wide range of viscosity. Low viscosity products (oils) A suitable piston pump system can be filled into a thick paste. Highly accurate piston and sealing systems, as well as variable nozzles with different flow openings, are the decisive factors in the successful processing of the product. During the product replacement period, the filling system that covers this broadband without the operator\'s input for major system modifications will be accepted by the market for a long time. High flexibility and cost for users-effectiveness. Liquid Tracking usually, a problem of thread formation occurs in the delivery of the product to the opened capsule. This is easy to solve when using a servo motor; The movement of the filling needle is coordinated to break the delivery line and prevent contamination of the product at the transfer point. The same system solves things like product post-dripping. Here, through the default system- Control the action, withdraw the drops formed after the product is delivered, and prevent uncontrollable drops. This process avoids unnecessary product contamination and produces a very consistent filling weight. In most applications, a constant product temperature is required throughout the product filling process- From the product container to the filling needle. [Tolerance often+ or -]1[degrees] Need to be careful * because the exact melting point of the product mixture must be treated and maintained to produce the correct combination of personal ingredients; * This way the product will not overheat unnecessarily because it will have a negative impact on the product (oxidation); * This way the filled capsule can cool down. Here, product- Heating system based on heating The water bath tank regulated by the machine control system allows for a constant height and a product- Save temperature control. It is usually advantageous to have two separate adjustable heating loops. This allows for individual temperature adjustment of the entire product line from the product container to the pump assembly. Constant Temperature Control has a decisive impact on the quality of the final product. The reliability and repeatability of the system settings populated through the product database are generally determined by easy-to-useand self- Explanatory machine control included in the product- Related database This includes product name, filling quantity/quantity, capsule size and filling temperature-- Including tolerance-- And products- Specific motion parameters Before each batch is processed, the operator can select the correct and predefined system settings for their respective products without mistake. In this way, mistakes ensure the highest level of drug safety Free production of qualified and verified filling processes. The degassing of the degassing product solves the problem of capsule bursting after the infusion process. This simple technique can influence the whole process decisively. When degassing, the product will simply separate the SAC part after closing. Again and again, it is clear that the closing procedure should be carried out in two phases. Thisso- The so-called pre-closure allows the establishment of positive pressure Before the final closure, the capsule cap and body were added to escape. These products are mandatory generic process solutions Specific solution systems are just a few technological innovations that suppliers offer to ensure a reliable and safe filling process. However, in addition to these products, A specific point requires the production of machines to provide a common process solution. This means an ergonomic design for short conversion, setup and cleaning times to ensure high productivity. Connection to downstream devices is also critical. Small functions such as not filling lost capsules (no capsule-- No fill function) It also provides operators with the advantage of minimal product loss and minimal pollution risk. PAT has been particularly enthusiastic since the launch of the FDA. There are some systems that can control the whole process and improve the process understanding, thus significantly improving the quality of the product. Now, the standard is continuous production documentation. The trend of filling liquid products into capsules is to gather momentum and provide users with technical solutions for many filling processes. [ Slightly] Illustrations For more information about capsule packaging technology, pharmaceutical solid Felix, product manager, Felix Nink Robert Bosch caps. Nink @ boschpackaging. com www. boschpackaging.