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Current and Future Manufacturing Processes of Personalised Medicine

Info: 5338 words (21 pages) Dissertation
Published: 10th Dec 2019

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Tags: Manufacturing

Content:

  1. Overview of need for personalised medicine
  1. Introduction
  2. Mind-map
  1. Regulation
  1. The need to switch from batch to continuous manufacturing
  2. History of regulation
  3. Advantages of continuous manufacturing
  4. Process diagram
  1. Manufacturing
  1. Manufacturing routes
  2. Understanding and isolation of the significant component
  1. Hot-melt extrusion (HME)
  1. Understanding how HME works
  2. Exploring the components of HME
  1. Rheology
  1. Mathematical description of how viscosity of the polymer melt behaves in the HME.
  1. Case studies of HME used in personalised medicine
  1. Application in dissolution rate change
  2. Application in taste masking
  3. Application in targeted drug delivery
  4. Application in nanotechnology
  5. Application in 3D printing and the potential of polypill technology.
  1. Pharmacometrics
  1. Pharmacokinetics analysis of targeted drug delivery system
  2. Its application towards personalised medicine
  1. Conclusion
  2. References

Introduction:

The demand for highly engineered drug products is on the rise. With the percentage of drug success in patients dwindling, it is becoming increasingly clear that there is a real need for patient-centric medication. The factors of which dictate the design of the medication are numerous but do show variance between patient to patient (see Fig. 1). This essay explores the innovative technological solution of hot-melt extrusion (HME) to manufacturing these medicines on demand.

Fig. 1, Node-link diagram of factors involved within the design of personalised medicine.

The pharmaceutical industry is in need of change. This is due in part to the practices employed by the pharmaceutical manufacturing industry. These manufacturing processes are relatively inefficient and poorly understood in comparison to other chemical process industries (McKenzie, Kiang, Tom, Erik Rubin, & Futran, 2006). This is mainly a consequence of the design of the pharmaceutical process. Furthermore, as new drugs are required to undergo the clinical trial procedure, this limits the available resources that could be used to advance the process development pipeline (Reinhardt, 2001). Moreover, given the unique chemical and physical properties of each active pharmaceutical ingredient (API) used this can affect the success rate of various drug product formulations and manufacturing routes (McKenzie et al., 2006). Because of the aforementioned challenges, sequential scale-up of batch processes remains the predominant process development trajectory within the pharmaceutical industry (Reinhardt, 2001). As a result, the manufacturing processes are not robust enough nor efficient. Under the current process development paradigm, manufacturing costs consume a large proportion of revenue for many pharmaceutical companies, as much as 27% by some estimates (Basu, Joglekar, Rai, Suresh, & Vernon, 2008). Other studies have noted that manufacturing can cost significantly more than research and development (Basu et al., 2008; Reinhardt, 2001). Insufficient understanding of the process can also create variability in product quality (Plumb, 2005). To meet the challenges that confront the pharmaceutical industry it must invest in more efficient and reliable technologies to ease the pressure of the economic and regulations that burden it (Buchholz, 2010; Plumb, 2005). One methodology that could be an applicable solution is continuous manufacturing (CM). This has the potential to address the limitations surrounding cost and robustness in the development of manufacturing processes without jeopardizing product quality.

Regulation:

Traditionally, the pharmaceutical and biopharmaceutical industries were not at the forefront of innovative engineering solutions and new principles within the field of chemical engineering. For many decades, the manufacturing of drug products was controlled by a regulatory framework that safeguarded the quality of the final product and performed testing of batch-based operations, raw material and end-product characteristics, fixed processed conditions, and in process material. As a result, limitations for the manufacturing of small molecule and biopharmaceutical products are widely acknowledged (Rantanen & Khinast, 2015). Critically this includes very long setup times, clean-down periods, and pauses in production while quality test result are being generated. These all add significant delays to production schedules, and lower utilization rates. Furthermore, these effects are exacerbated for products with multiple dose strengths and low production volumes. Clearly, these activities are essential, but these operations are not direct production activities and so reduce overall plant utilization (M.W.Wilson, 2016).

However, in recent years there has been a growth of interest in increasing the safety and quality of drug based medications whilst simultaneously reducing the cost of the manufacturing process by employing more structured pharmaceutical development and manufacturing approaches. A recent implementation of this is the use of the United States Food and Drug Administration (US FDA) process analytical technology (PAT) guidance and quality by design (QbD) approach by the International Conference on Harmonization (ICH) framework ICH Q8 R2 2009 (Rantanen & Khinast, 2015). This has introduced the concept of real-time process control and real-time quality assurance that fulfils predefined product quality on a continuous basis, e.g. continuous manufacturing (CM). The benefits of switching from batch to continuous from an economic perspective include, that it uses equipment on a much smaller scale. This corresponds to a reduction in capital spent on equipment, increase in available plant space and lower utility requirements (Centaur Media plc group, 2015). Continuous process scale readily, therefore this can be seen as an advantage due to batch process being unable to scale because of operating time and parallelization of which require further studies to be undertaken. Hence, this can reduce time to market, which in turn may increase competitions free lifespan. The amount of API passing through a continuous process can also be reduced due to rapid data production, which could be seen as a cost saving procedure if the API commands a high supply fee (Aksu et al., 2012; Plumb, 2005; Schaber et al., 2011; Shah, 2004). Finally, continuous manufacturing can decrease product variation, thereby mitigating the underlying issues associated with batch with in-line process control (Aksu et al., 2012; Buchholz, 2010; Plumb, 2005). Moreover, the reduction in batch-batch variability removes the need to take samples to conduct off-line analytical testing which is time consuming, expensive and inefficient. The use of on-line process controls enables the quality of the end product characteristics to be predictable (Tominaga, Langevin, & Orton, 2015).

The ICH is in the process of creating a new regulatory framework (ICH Q12) that will be the basis of allowing CM to be spread across the industry worldwide.

Fig. 2, Process flow diagram of quality by testing (QbT)- batch in comparison to quality by design (QbD) – continuous (Yu, 2008).

The Manufacturing Routes:

Downstream pharmaceutical processes typically begin with the feeding of raw materials (API and excipients) to the process. The feed material is then by gravity passed through a comill to eliminate any large or soft lumps within the powder volume. Thereafter the material is blended to ensure uniform distribution of active ingredient. Alternatively, the blend may be pumped to a granulator to undergo wet or dry granulation. The use of wet granulation necessitates a granule drying step (controlled heating system) prior to further processing. If a granulation process has been used, a milling step is typically introduced to reduce the granules to the desired size before tableting. In the absence of a granulation step material may be sent directly to the tablet press after blending. In a continuous tablet press the powder is typically fed via a hopper and a rotary feed frame. The powder blend fills a die and is subsequently compressed to create a tablet (Rogers, Hashemi, & Ierapetritou, 2013).

Figure 3, Overview of the three main manufacturing routes are shown (Rogers et al., 2013).

Deconstructing the process route into its individual components we can focus on the piece of equipment that could be tailored for use on patients with specific needs, see table 1.

Table 1, Break of process units used in figure 3, with the twin screw extruder highlighted.

Hot-melt extrusion:

Hot-melt extrusion (HME) is an innovative technology for the production of new chemical entities in the pharmaceutical manufacturing pipeline, it also has the potential to improve existing products currently on the market (Patil, Tiwari, & Repka, 2015). It involves the application of heat to melt a polymer and force it through an orifice in a continuous process. In terms of pharmaceutical application, it is used to create a solid dispersion of an API. The reason for doing this is that more than 50% of APIs currently on the market belong to the biopharmaceutical classification system II (BCS class II) which are characterized as poorly water-soluble compounds and results in formulations with low bioavailability. Therefore, by converting the ingredients poorly water-soluble crystalline form to a dispersion, the compound becomes amorphous which has the properties of increased solubility and bioavailability (Patil et al., 2015).

HME is carried out using an extruder – a barrel containing one or two rotating screws that transport material down the barrel. Extruders consist of four distinct parts (Particle Sciences: Drug Development Service, 2011):

  1. An entry point through which the contents enters the barrel, that is connected to a hopper unit that is filled with the materials to be extruded, or that may be continuously supplied to in a controlled manner by one or more external feeders.
  2. A conveying section of which comprises of a barrel and screw that transports the material, and where applicable, mix the material.
  3. An orifice for the shaping the material as it exits the extruder.
  4. Downstream auxiliary equipment for cooling, cutting and/or collecting the finished product.

Image result for hot melt extrusion
The HME process is illustrated in Fig. 4 and process step 4 is shown in Fig. 5 displaying the various shapes the extrudate can be transformed into.

Figure 4, Hot melt extrusion process diagram (ThermoFisher Scientific, 2017).

 

Figure 5, downstream process options of HME (Tiwari, Patil, & Repka, 2016).

There are two types of extruders: single and twin-screw extruders, see Fig. 6. Each extruder has a modular design, allowing interchangeability between different sections of the extruder (feed, transition and metering zones). Therefore, the screws can have varying pitches, which for each section serve a different purpose (Breitenbach, 2002). Single screw extruders are mainly used for melting and conveying polymers to extrude them into continuous shapes, whereas twin screw extruders are used for mixing polymers with additional materials such as APIs and for devolatilization. This mixing creates a polymeric matrix where the API molecules are distributed within, created a true molecular solution. As a result, the production of pharmaceutical formulations which require homogenous and consistent mixing of multiple formulation ingredients, a twin-screw extruder is emerging as the most viable option. (Particle Sciences: Drug Development Service, 2011).

Melting is accomplished by frictional heating within the barrel, and for twin-screw extruders, the materials are subject to a shearing force by the rotation of the screws and between the screws and the wall of the barrel as they are conveyed. This generates as much as 80% of the heat required to melt or fuse the material. The barrel is also heated with electrical heaters mounted on the barrel, or cooled with water. Viscosity is another paramount factor when undergoing the process and therefore an optimum temperature is selected so the contents do not     become to viscous (Particle Sciences: Drug Development Service, 2011).

Figure 6, inside view of single and twin-extruder screws (Particle Sciences: Drug Development Service, 2011).

 

 

 

 

Mass flow during hot-melt extrusion:

Many polymer solutions, dispersions and melts behave as pseudoplastic (shear thinning) fluids under typical processing conditions. The shear rate (

γ) – shear stress (

τ) relationship of time independent non-Newtonian fluids can be described by the general equation (1) (Polymer DataBase, 2015):

γ=f(τ)                                                                                 (1)

Or graphically (see fig. 7):

http://polymerdatabase.com/polymer%20physics/images/FluidTypes.png

Figure 7, graphs of relationship between shear stress vs shear strain, apparent viscosity vs shear strain (Polymer DataBase, 2015).

http://polymerdatabase.com/polymer%20physics/images/Non-Newtonian.pngThe observed pseudoplastic behaviour of polymer melts are caused by the disentanglement of polymer during shearing. Polymers with high molecular weights are generally always entangled at rest. During flow this entanglement becomes more orientated and aligned, which in turn, causes the viscosity to drop. The degree of alignment will increase with increasing flow. At sufficiently high shear rates, the flow will become independent of shearing rate. The same is true for very low shear rates; the polymer chains move so slowly that entanglement does not impede the shear flow. The viscosity at infinite slow shear is called zero shear rate viscosity (

η0). The typical behaviour is shown in the graph, see fig. 8 (Polymer DataBase, 2015)

Figure 8, graph of apparent viscosity vs shear rate for polymer melt (Polymer DataBase, 2015).

The viscosity of a pseudoplastic fluid depends upon the shear rate and is described by the following power law equation (2) (H.A. Barnes, 1989):

η=K(T) x γn-1                                                                              (2)

Where;

η

= apparent viscosity of polymer melt (Pa.s)

K

= exponential function of the temperature (T) (Pa.sn)

γ

= Shear rate (s-1)

n

= flow behaviour index or power law constant (dimensionless)

Advantages of using HME compared to other manufacturing techniques include that it does not require the use of a solvent. As a result, the associated solvent-stability risks that can occur during shell life of the formulation are avoided as there is no residual solvent (Patil et al., 2015). Furthermore, this reduces the number of processing steps and eliminating time consuming drying steps (Crowley et al., 2007). The residence time from start to finish is usually within the order of minutes and this helps to avoid thermal degradation of the ingredients. The process is conducted in dry conditions which makes it suitable for moisture sensitive drugs. It can provide taste masking of poorly tasting APIs and is an easy, reliable way to achieve prolonged drug release. Reduced risk of dose pumping compared to coated monolithic systems (C.W. Brabender Instruments, Inc., 2011).

Case studies of HME in personalised medicine:

Dissolution rate change:

(Hülsmann, Backensfeld, Keitel, & Bodmeier, 2000) conducted a study of the HME technology to affect dissolution rate change by varying the compositions used in the extruder. The main assay was the poorly water-soluble drug 17β-estradiol hemihydrate. This was introduced into the extruder with excipients Sucroester WE15 and Gelucire 44/14. The polymers used were PEG 6000, PVP, or a vinylpyrrolidone-vinyl acetate. The results showed that the solid dispersion created was of a higher dissolution rate in comparison to that of the pure drug alone or the physical mixtures. A 30-fold increase in the dissolution rate was obtained for the formulation containing 17β-estradiol, PVP, and Gelucire 44/14 at 10%, 50%, and 40%, respectively. Downstream, the mixture was tableted, and further studies showed the dissolution rate was consistent when administered.

Targeted drug delivery:

(Bruce, Shah, Waseem Malick, Infeld, & McGinity, 2005) used the HME to personalise the drug delivery profile in the colon. The assay being used was 5-aminosalicylic acid (5-ASA). The polymer to carry the drug was Eudragit® S 100 of which was also coupled with plasticizers triethyl citrate (TEC) and citric acid. It was found that the TEC decreased the processing temperature and had an effect on the drug release rates which was previously plagued by earlier than expected leaching. Ultimately, the citric acid content reduced the pH of the micro-environment of the tablet, thereby suppressing the polymer ionization which resulted in slower drug release rate.

Taste Masking:

(Maniruzzaman et al., 2012) studied the HME technology as a solution to improve the taste characteristics of the medicine paracetamol. This was achieved by preparing a blend with polymers Eudragit E PO and Kollidon VA 64. The screw profile was that of a twin-screw extruder. The type of module used was a Turbula. Different drug-polymer compositions were used (drug/E PO and drug/VA 64 at ratios of 40/60, 50/50, and 60/40 and 30/70, 40/60, and 50/50, respectively). The extruded granules of paracetamol mixture were then used in a further study with six healthy human volunteers to see whether taste had improved or not. This study concluded that taste had improved and this was supported by e-tongue sensory equipment that generated a positive correlation. The highest taste-masking effect was observed with Kollidon VA 64 at 30% drug loading.

Nanotechnology:

(Patil, Kulkarni, Majumdar, & Repka, 2014) explored the potential application of HME in conjunction with a high-pressure homogenizer to produce solid lipid nanoparticles (SLN) as a drug carrier system. The assay in question would be fenofibrate which is classed as a poorly water-soluble drug by BCS class II which also has low bioavailability. The particle size of the pre-emulsions produced using the HME and a conventional method was 653 and 1643 nm, respectively. An advantage concluded from the study showed that the conventional method required a number of iterations of use to be able to achieve particles sizes in range of >200nm. Therefore, HME process proved that when used together with the high pressure homogenizer the pre-emulsion already had a size in the low nanometre range. An in vivo study showed that the plasma concentration of metabolite fenofibric acid was significantly higher (P<0.05) in rats treated with fenofibrate SLN than those with commercially available fenofibrate.

3D Printing:

HME is one of the most commonly used techniques to create fused filaments, and it can therefore be used to create filaments that can be directly introduced in a 3D printer to create the desired shape and geometry of the pharmaceutical dosage form (see fig. 9). Recently, (Pietrzak, Isreb, & Alhnan, 2015) developed a flexible-dose dispenser for immediate- and extended-release 3D-printed tablets. The authors combined HME (HAAKE MiniCTW extruder) with 3D printing to prepare 3D-printed theophylline tablets. The authors used different polymers, such as methacrylic polymers (Eudragit® RL, RS, and E) and cellulose-based polymers (hydroxypropyl cellulose, HPC SSL), to prepare HME-theophylline extrudate filaments (1.5 mm in diameter). The drug-loaded Eudragit® filaments were subsequently introduced in the 3D printer, and caplet designs of different dimensions (mass and volume) were printed with the aid of a computer software. Differential scanning Calorimetry thermograph and x-ray powder diffraction analysis showed that the majority of the theophylline in the 3D-printed tablets was in the crystalline form. The tablets had an extended release over 16 hours. These results showed that the drug release profile of the 3D-printed tablet was dependent on the drug loading of the tablet. Low drug-loading tablets (60 mg and 125 mg) showed faster drug release compared to that of high drug-loading tablets (300 mg). Coupling HME with 3D printing provides the added advantage of producing single tablets with very high drug-loading capacities. This may greatly improve patient compliance, as patients only need to take one dose a day rather than small doses several times a day. Since patient compliance still is one of the main factors negatively affecting the therapeutic efficacy of a wide range of drugs, this hybrid manufacturing system may contribute to addressing this important issue.

In summary HME presents a credible solution to the manufacture of specifically orientated medication on demand while being mobile as technology.

Figure 9, Illustration of the fabrication of different sizes and shape tablets by HME technology coupled with 3D printer (Tiwari et al., 2016).

With this coupled technology in mind, it should be noted that this could be expanded to incorporate the potential of ‘polypill’ technology. Polypill technology is essentially combining multiples APIs into one tablet. The benefits of such tablet design include lower patient adherence (less likely to miss scheduled doses), reduction in pill burden on elderly patients and more convenience in use. The technology relies on the manufacturing principle of “postponement of complexity”, in order to allow the creation of individualized combination to tablets to be a practical possibility. A machine selects the required tablets according to a patient-specific order in the control system (HME-3D printer setup), and adds a pharmaceutical grade bonding agent to join each pair of tablet elements (see fig. 10). In this fashion, a triple layer tablet could be assembled for a patient. The polypill could then be packaged into a blister pack that has labelling orientated towards the specific patient. The pack could then be either be mailed or picked from a local retail pharmacy operation (M.W.Wilson, 2016).

Figure 10, Assembly of individualised polypills at distribution site (M.W.Wilson, 2016).

Pharmacometrics analysis of targeted drug delivery:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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