Quality by Design Considerations for the Development of Lyophilized Products

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Quality by Design Considerations for the Development of Lyophilized Products Alina Porfire, Ioan Tomuta, Sonia Iurian, Tibor Casian Department of Pharmaceutical Technology and Biopharmaceutics, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj Napoca, Romania

1 INTRODUCTION Lyophilization or freeze drying is a process traditionally used for stabilization of drugs, which starts with freezing a solution of the drug and continues with solvent removal by sublimation and subsequently by desorption.1 The process relies on heat and mass transfer and is divided into the following unit operations: freezing, primary drying, and secondary drying. During the freezing step, the lowering of temperature leads to the formation of ice crystals and the product is frozen. However, a part of the solvent is retained in a bound form to the formulation constituents. Primary drying is initiated by decreasing the chamber pressure and heating the sample which leads to ice removal by sublimation.2,3 In this phase, the objective is to ensure a product temperature below the critical temperatures and a minimum process length, thus reducing the manufacturing costs.4 The secondary drying involves a temperature raise to 25°C or higher and maintaining it for several hours, ensuring the removal of bound water by a desorption mechanism. Compared to the primary drying, higher temperatures are used and pressure is not an important factor in the secondary drying.5 Lyophilization has a wide range of pharmaceutical applications. The oldest applications are the drying of labile pharmaceutical products, like parenteral antibiotics, proteins, and vaccines, which are reconstituted prior to administration. Nowadays, the spectrum of applications has broadened, and includes preparation of various “novel” lyophilisates, such as threedimensional (3D) scaffolds, orally disintegrating tablets, respirable powders, and various nanoparticulate delivery systems.6 Consequently, the need to develop optimized formulations and lyophilization processes has increased in the same manner. In this regard, the implementation of the quality by Pharmaceutical Quality by Design https://doi.org/10.1016/B978-0-12-815799-2.00011-3

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design (QbD) principles facilitates process understanding and development of high-quality lyophilized products. The QbD concept requires that the product and the process should be scientifically designed to meet predefined objectives instead of having their quality confirmed in the final stage of the preparation.7 Thus, the design space (DS), defined as the multidimensional combination of factors that grants quality assurance, can be built through the data provided by the process development and optimization studies, which establish factor and product quality interrelation.8 The application of the QbD principles has gained attention in the last few years to improve the quality of lyophilized products by controlling the formulation and process variables. This chapter provides information and perspectives regarding these applications in the development of the lyophilization process as well as of the novel products obtained through lyophilization, i.e. oral lyophylisates and lyophilized liposomes.

2 DEVELOPMENT OF LYOPHILIZATION PROCESS The QbD concept can be applied to gain knowledge in the field of freeze drying by implementing a process monitoring method coupled with a control system or through the definition of DS. The process monitoring instruments are used to record the product temperature in various shelf positions, pressure change, water content, and heat and mass transfer. The obtained data, further processed by mathematical methods, allows product evaluation, defining the operating conditions, and confirming standard process evolution.2,9 The freezing step, through the used freezing rate and nucleation temperature, has an influence on the ice crystal size, product porosity, product morphology, and also on further processing during primary/secondary drying. These characteristics of the system can be linked to stability issues, drying rates, residual moisture, and cake appearance. Large ice crystals lead to large pores which will offer a fast sublimation during the primary drying, but a slow desorption in the secondary drying.10 Using the experimentally determined distribution of nucleation temperature with a freeze-drying dynamic mathematical model, intra /inter-batch vial heterogeneity of the product morphology could be predicted. Knowing the heterogeneity of the pore diameter, the product resistance to vapor flow and drying time variability can be calculated. Through this concept, Capozzi et al. compared two freezing configurations (conventional and

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suspended vial freezing), highlighting a reduced intra-/inter-vial heterogeneity and larger pores for suspended vial configuration.10 Arsiccio et al. applied the computational fluid dynamics simulations to predict temperature profiles during the freezing step and determined the freezing front velocity and temperature gradients that influence ice crystal size. The DS for the freezing step is a contour plot representing the cooling rate against nucleation temperature, showing their impact on the ice crystal size, the duration of primary drying, and the maximum temperature reached by the product during primary drying.11 The primary drying is the lengthy phase where most of the solvent is removed, associated with an increased risk of batch failure. Shelf temperature and chamber pressure are the influential factors affecting the efficiency of water removal. Shelf temperature has to be selected so that the product temperature is kept below critical values to avoid liquid-phase formation (crystalline) or product collapse (amorphous system).2 The cycle development also has to consider the equipment constraints. Knowing the maximum mass flow rate that can be efficiently condensed is beneficial in avoiding a choked flow and unnecessarily low pressures. Giordano et al. applied mathematical models to construct the DS for primary drying enabling the identification of operating conditions by applying constraints on the maximum product temperature and sublimation rate, and minimum achievable drying time.2 Appropriate implementation of the freeze-drying models for DS calculations involves an accurate estimation of aforementioned process parameters, as their uncertainty influences the range of operating conditions and the area with low risk of failure. The inter-vial variability in heat transfer coefficient (vial positioning) and product resistance (size and shape of ice crystals) can be accounted for by considering a distribution around mean parameter values estimated experimentally, by calculating variance or though uncertainty analysis extended with error propagation.2,12–14 The heat transfer coefficient at a certain pressure can be estimated using gravimetric method, Pressure Rise analysis, Dynamic Parameter estimation, Manometric Temperature Measurement, and Tunable Diode Laser Absorption Spectroscopy (TDLAS). The Product resistance to sublimation can be estimated using product temperature measurements, pressure rise test, TDLAS, or a weighing device that measures both temperature and weight loss.9 Fissore et al. proposed a three coordinate diagram built using chamber pressure, shelf temperature, and dried layer thickness taking into account the time dependency of the DS. As dried layer thickness and resistance of

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the product can influence product temperature and sublimation flux for defined operating conditions, the product can be found within the DS at a certain time and outside at a different time.12 To keep the product temperature under the critical value, the optimal operating conditions change in time, thus DS has a dynamic nature.14 The diagram provides a good tool for recipe design, optimization, and process failure analysis. Applying the proposed concept for building the DS, the primary drying time of a process could be efficiently reduced by allowing more aggressive drying conditions in the initial part of drying.12 Vial-to-vial sublimation variability has been observed for vials within the same batch due to differences in nucleation and ice crystal formation. Scutella et al. evaluated the average evolution of product resistance as a function of dried layer thickness (pressure rise test) and local variability of mass loss at a certain dried layer thickness (single vial gravimetric method). The stoppers did not influence the sublimation rate, and the freezing protocol presented an effect. Applying the controlled ice nucleation in the freezing phase lead to an improved mass flow rate and lower variability compared to spontaneous nucleation, considering the reduced product resistance variability. Based on the product resistance variability, a product temperature distribution was calculated allowing the definition of the risk of failure.13 Patel et al. proposed for the definition of the DS the graphical representation of mass flux as a function of chamber pressure. By delimiting the regions imposed by equipment constraints and chocked flow regions, the operational space could be identified. As the product temperature is defined through shelf temperature and chamber pressure, using shelf temperature isotherms the operating conditions could be defined, which ensured the product temperature within the desired interval. During primary drying, the shelf temperature and chamber pressure vary around a set point due to the inability to maintain fixed values, thus a new region can be defined within DS, known as control space. The set point should be selected considering the known parameter variation to ensure short cycles and the localization of the control space within the the DS.3 Zhu et al. coupled computational fluid dynamics with the heat and mass transfer modeling to predict independent variables (shelf temperature, chamber pressure) and response variables (product resistance, product temperature, and drying time) for lab- and pilot-scale equipment. Models were applied to construct DS for a product and were successfully confirmed through experiments.15

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Using mechanistic models to describe and approximate processes can be useful for the identification of influential process parameters. To ensure an appropriate modeling, the use of global sensitivity analysis (GSA) can be applied to evaluate how uncertainty in response variables can be divided into different uncertainty sources from the input variables. Moreover, it can be used to highlight the variables for which the uncertainty level does not affect the output result, and the variables for which reducing the uncertainty would impact the output, thus can measure the associated risk of failure.16 The GSA application demonstrated that temperature at sublimation front and sublimation rate are mostly influenced by shelf temperature, a factor presenting a decreasing impact considering that product resistance increases in time and the input energy should be lowered to avoid cake collapse. The chamber pressure influenced mainly the temperature at sublimation front, whereas dried product mass transfer resistance influenced the sublimation rate.16 Ohori et al. investigated the effect of temperature ramp rate in the initial part of the primary drying on a model cake (trehalose 10%) considering that this parameter is usually not evaluated. Applying a slow ramp rate led to the collapse of the cake attributed to an increased product resistance, slower sublimation and thus a less efficient water removal.17 Product load variation can also impact vial heat transfer coefficient, product temperature, and drying time through the presence of radiation effect. This factor does not induce freezing variations and residual water content variations.18 For primary drying it is recommended to calculate a DS for each group of vials based on heat transfer coefficient considering regions that differ in the amount of received heat—radiation from chamber wall, conduction through contact with other vials, or metal frames.12 The objective of secondary drying is to remove the bound water by desorption in order to ensure the desired residual moisture in the product.5,19 As drying proceeds and water content decreases, the maximum temperature that the product can be exposed to, increases. So, the cycle may be optimized considering the time dependency of the critical temperature.5 Mathematical modeling of the relation between temperature of the product and residual moisture vs shelf temperature and time allowed the development of DS for this phase. Two important parameters for calculations were the heat transfer coefficient and kinetics of water removal. Considering the inter-vial heterogeneity it is possible to calculate various DS,

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thus having the possibility of defining the operating conditions that allow critical vials to dry efficiently.5 The efficient cycle design and optimization can be addressed also through the use of process analytical technology (PAT) concept. In this respect Bosca et al. applied a soft sensor as PAT instrument making possible the calculation of mass transfer flux, residual ice level, and heat and mass transfer coefficients. The smart soft sensor comprises a temperature measuring device, mathematical model and the extended Kalman filter algorithm. The authors accomplished the definition of freeze-drying parameters through one-cycle only without preliminary investigation and multivariate optimizations.9 De Beer et al. applied Raman, NIR and Plasma Emission Spectroscopic methods combined with the design of experiments (DoE) for formulation and process optimization purposes. The use of DoE, innovative process analyzers, and offline product characterization methods identified the influence exerted by process and formulation factors over critical responses. The DS was defined through the developed models and Monte Carlo simulations evaluating the risk of obtaining a product with quality profile outside the acceptance limits.20

3 DEVELOPMENT OF ORAL LYOPHYLISATES Oral lyophilisates (OLs) are solid oral dosage forms obtained by the freeze drying of drug solutions or suspensions.21,22 They emerged from the plethora of patient centered dosage forms and display both the advantages of solid dosage forms and those of liquid preparations.23 The short disintegration time is their most important quality attribute, as a few seconds are enough for the product to dissolve or disperse into the saliva. Moreover, they ensure precise dosing, high stability, and ease of swallowing without the need of water ingestion and sometimes have better bioavailability.23,24 However, the OLs are fragile products that require special packaging, are very hygroscopic, only the low dose APIs can be formulated as OLs, and they sometimes require taste-masking techniques.25–27 Their preparation consists of dissolving or suspending the active pharmaceutical ingredient (API) in a polymer solution. The polymer acts like a matrix-forming agent for the freeze-dried cake. A bulking agent is also necessary to yield the appropriate mechanical strength and polyols were frequently used as bulking agents.21 Additionally, stabilizers, surfactants, pH

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buffers, sweeteners, and other excipients can be associated. The resulting product is further poured into blister sockets, submitted to a freeze-drying cycle, and then sealed with an aluminum pellicle. Its final characteristics depend on the API physical and chemical properties, the chosen formulation and the lyophilization process parameters.28 For the development of OLs in the QbD paradigm, the first stage is setting the quality target product profile (QTPP). As a quality control measure, the regulating authorities included limitations regarding the disintegration time of OLs: maximum 3 min mentioned in the European Pharmacopeia, maximum 30 s in the Food and Drug Association (FDA) guidelines, and variable limits as a function of drug product in USP.29 Iurian et al. established the set of quality criteria desired for OLs with meloxicam out of literature data and marketed products measurements. Out of the QTPP, resulted the critical quality attributes (CQAs) and the limits within which they could vary. The aspect of the cake was supposed to be neat, with no visible fractures. The disintegration time was set below 25 s, associated with mechanical strength and fracturability higher than 15 N and more than 90% of dissolved API after 30 min. Further, DoE was used to investigate the connection between the input formulation and process variables, and the output variables, the OL’s CQAs. Apart from the expected excipient effects, DoE methodology highlighted the interactive effect of methylcellulose (MC), the matrix-forming agent, and of the type of freezing, on API dissolution: at constant MC ratio the shelf-ramped freezing improved the API dissolution, while fast freezing flattened the effect of MC ratio increase. The generated DS included multiple combinations of formulation factors and freezing rates that could be done to comply with the QTPP limitations, meaning a highly flexible process that grants constant quality end products.30 This study indicated that both formulation factors and lyophilization parameters should be thoroughly controlled in order to obtain the desired quality features: the freezing step regulates ice crystal size, thus final product porosity and hydration properties. These effects were further investigated by the same research group in a DoE that associated fast freezing, progressive freezing, and annealing with two matrix-forming agents at different ratios: sodium croscarmellose and sodium alginate. From the evaluated CQAs, disintegration and API dissolution were influenced by all the factors, showing that the association of annealing during freezing stage and a low ratio of sodium alginate leads to products within the QTPP. The validity of DoE predictions was confirmed by preparing and testing the recovery of formulations from the generated DS.31

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The easy administration of OLs recommends them for pediatric patients who may face difficulties with conventional solid dosage forms intake. In this respect, Casian et al. proposed the development of pediatric OLs with loratadine. Apart from the features that were previously included in the QTPP, the pediatric use requires a minimum number of nontoxic excipients. For the product to comply with all the conditions, a quality risk assessment coupled with quality risk management was applied. An Ishikawa analysis helped the identification of all the parameters concerning formulation, preparation, freeze-drying process, and analytical methods that could have an impact on the CQAs. Failure model effects analysis (FMEA) was used to sort the parameters and those with the highest risk score were the type and ratio of bulking agent and matrix-forming agent. Therefore, as a risk-reduction strategy, a screening DoE was developed to choose from a wide list of excipients, followed by an optimization DoE where only the excipients found appropriate: sodium alginate and xanthan gum for matrix-forming agents and mannitol for bulking agent, were included. From the information gained in the screening design, during the optimization the disintegration time was reduced from 160 s to less than 60 s. The data analysis by response surface modeling (RSM) showed that mannitol reinforces the structure but hinders water uptake and disintegration. Thus, the DS indicated optimal formulations obtained with the intermediate levels of mannitol and high ratios of xanthan gum.32 Florez Borges et al. performed a preformulation study of an OL with cetirizine dihydrochloride as an active ingredient. As a QbD tool, they used SeDeM methodology to characterize the API, a development method that enquires the CQAs of the API with a potential impact on the final product, which was previously applied on powders for direct compression. Lyophilization has been proposed as a process that would overcome the APIs poor compressibility features. SeDeM diagram provided stability data regarding the API’s humidity of 0.150% and spontaneous hygroscopicity of 0.200% which recommend the API for this dosage form.33 AlHusban et al. aimed at preparing a multiparticulate system consisting in omeprazole pellets coated with an enteric film included in a fast disintegrating freeze-dried matrix. The DoE coupled with RSM was applied to assess the influence of several variables on OLs’ disintegration time and hardness. Viscosity and pH were also considered key features of the product: high viscosity was needed to prevent pellet sedimentation, whereas the pH was meant to ensure pellet stability in gastric conditions. Three quantitative variables were evaluated: concentrations of gelatin as matrix forming agent,

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concentrations of carrageenan as suspending agent and concentrations of alanine as matrix supporting/disintegration enhancing agent.34 Gelatin behavior in OLs was widely studied, since gelatin was the main component of Zydis, the first patented oral lyophilisate.35 But its interaction with other excipients required a complex study design that led to the development of a central composite face centered design. Hotspot analysis allowed the preparation of an optimal formulation with minimum disintegration time, but maximum hardness and viscosity. OLs are often prepared from freeze-dried suspensions, thus it is highly probable to obtain an inhomogeneous product due to API sedimentation. As a nondestructive PAT tool, Chiriac et al. used NIR Chemical Imaging to assess API homogeneity in OLs with acetaminophen and pregabalin. They applied PLS—discriminatory analysis on the full range of NIR spectra without prior wavelength selection and demonstrated that the API content was in good agreement with the drug ratio used for the preparation.36

4 DEVELOPMENT OF LYOPHILIZED LIPOSOMES One of the most recognized strategies for drug delivery using nanosystems is the encapsulation of the active ingredient in liposomes. Liposomes are vesicles composed of a bilayer and/or a concentric series of multiple bilayers separated by aqueous compartments formed by amphipathic molecules such as phospholipids that enclose a central aqueous compartment. They encapsulate water-soluble drugs and hydrophobic drugs.37 Besides the demonstration of safety and efficacy, there are several major obstacles in their large-scale fabrication and clinical application, such as the reproducibility of the manufacturing process and destabilization of their structure during long-term storage, when formulated as aqueous dispersions.38,39 In this regard, lyophilization has been proposed as a promising direction to overcome the stability problems. By lyophilization, the final product is preserved in a dried state that is, freeze dried with cryoprotectants and is reconstituted with solvent immediately prior to administration.38 Despite this advantage, the lyophilization process itself may affect the quality of the final product. If the lyophilization process is conducted in the absence of added excipients that preserve the bilayer structure, they coalesce and aggregate and the included water-soluble drug leaks out.40 Consequently, optimization of the formulation and process parameters are the key elements to maintain the quality of the final product. The objectives of the optimization study have to be the protection of the lipid bilayers from the damage caused by

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the ice crystals during freezing, inhibition of vesicles fusion or aggregation following dehydration, and the avoidance of a phase transition during rehydration.41 Implementation of the QbD in the development of lyophilized nanoliposomes should start with identifying the QTPP, taking into account the efficiency and safety of the product. In general, liposomal products are designed for systemic administration, the intravenous route being the most used.42 The accurate identification of CQAs is crucial to perform relevant predictions of the quality and safety. The following are considered as quality attributes (QAs) of liposomal products: particle size, polidispersity index (PDI), morphology, phase transition temperature, surface charge (in the form of zeta potential), encapsulation efficiency, leakage rate of the drug through shelf life, liposome structure, and liposome integrity changes.37 These quality attributes must be ranked with respect to their criticality in terms of product efficiency and safety.43 For the particular case of lyophilized liposomes, some of the mentioned QAs may change in response to the lyophilization process (i.e., size, particle size distribution, liposome structure and integrity, drug retention, and phase transition temperature), while others specific for the dried form should be added (i.e., cake appearance and moisture content). For example, for simvastatin-loaded long circulating liposomes, the size, drug liposomal concentration, and encapsulation efficiency were studied as CQAs.44 Further, when the same formulation was stabilized through lyophilization, the size, the drug retention, the change in transition temperature, and the moisture content were the CQAs.45 The size of liposomes influences both the drug release and the product efficacy, through its impact on biodistribution and drug pharmacokinetic. In this respect, the goal is generally to achieve a particle size range between 100 and 200 nm. Usually, the preparation method includes a size reduction step followed by uniformizing particle size through extrusion.42 Achieving a particle size below 200 nm is important from the technological point of view, as this size range would allow sterile filtration of the final product.46 In terms of efficiency, the passive tumor targeting for increased efficacy of chemotherapy, for example, is strongly dependent on the particle size.47 The drug encapsulation and retention are very important QAs, as increased concentration in the final product could reduce the manufacturing cost, allow greater flexibility in dosing, and increases patient compliance.46 Drug retention is considered as the most sensitive parameter reflecting the damage caused by lyophilization.48 To achieve higher drug retention, two events have to be avoided: fusion/aggregation of vesicles and reaching the

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phase transition temperature of phospholipids.41 Another essential QA is the moisture content; the acceptable content being below 3%, as low moisture content generally improves the drug retention and prevents any chemical degradations through hydrolysis.49 The influence of formulation and process parameters on the CQAs has to be established. In the QbD approach this is performed by DoE with the final goal to determine the product DS taking into account the accepted variability of the CQAs. The most influential formulation factors are the nature and concentration of the drug, the composition of lipid bilayers, the type and concentration of lyoprotectant, and the size of the vesicles. Regarding the process parameters, factors related to preparation method, size-reduction procedures as well as lyophilization steps have to be evaluated. The effect of the bilayer composition has been investigated regarding different phospholipids, the presence of cholesterol or cholesterol derivatives, and the presence of PEGylated phospholipids or charged phospholipids. As the leakage of the drug is strongly influenced by the transition temperature of the lipid, and this property varies with the acyl chain of the phospholipids, the nature of the phospholipid will influence the stability during lyophilization and long-term storage.41 The presence of cholesterol provides formulation benefits including good retention of encapsulated drug, but cholesterol-free liposomes are also very useful. Chaudhury et al. investigated the lyophilization of cholesterol-free liposomes loaded with carboplatin. Apart from drug retention, for the formulation lyophilized using sucrose as cryoprotectant, all the other QAs, namely the size, the polydispersity, and the morphology, were similar to the non-lyophilized formulation, and the water content was low. Therefore, the authors proposed the drug loading via the passive equilibration method as a strategy to prevent the drug leakage during lyophilization.50 Guan et al. showed that using sodium cholesterol sulfate instead of cholesterol for the preparation of nimodipineloaded lyophilized liposomes, smaller sized vesicles are obtained, with increased absolute zeta potential value, which would inhibit the vesicles fusing into larger ones.38 The usual approach to overcome the damages during lyophilization and rehydration is the addition of lyoprotectants, such as carbohydrates. Thus, the impact of the type and concentration of lyoprotectant is extensively explored. A study reports the influence of three potential lyoprotectants: sucrose, mannitol, and trehalose on liposome size on reconstitution after lyophilization, and only sucrose, in a sucrose:lipid ratio over 1:9, protected the liposomes from aggregation during storage.51 For another product a

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mixture of two cryoprotectants; mannitol and trehalose, gave better results by combining the bulking effect of manitol with the membrane-protecting effect of trehalose.38 Another study shows that the presence of an interior gelatin support has better protective effect than lyoprotectants against lyophilization stress.52 The knowledge gained through the previous studies is useful in the QbD approach to establish the material attributes and process parameters which may be critical for the quality of the final product, which should be evaluated through risk assessment or included in screening studies. Further, a deeper understanding of the potential interactions between the material properties and the process parameters is gained by the use of DoE and multivariate analysis. Finally, the determination of the DS is possible. Through this approach, Porfire et al. established the DS for the lyophilized long-criculating liposomes with simvastatin. The study explored the influence of several risk factors, both formulation and process parameters, on the CQAs of the product (the size, the drug retention, the moisture content, and the change in transition temperature), through DoE. After defining the desired response values and acceptable limits for CQAs, the DS was defined by evaluating the risk of getting product with quality profile outside acceptance limits.45 In a similar manner, Sylvester et al. proposed the DS for freeze-dried pravastatin-loaded long circulating liposomes. In this case, parameters related to the lyophilization process, namely freezing rate, shelf temperature during primary drying, and the presence of an annealing step, as well as various lyoprotectants were simultaneously investigated through a D-optimal experimental design. The model generated through DoE enabled the construction of a DS that guarantees to obtain liposomes with desired physicochemical characteristics (unmodified particle size and zeta potential, good drug retention), a moisture content below 2%, and elegant cake appearance along with an economic cycle time.53

5 CONCLUSIONS The QbD, a new approach to pharmaceutical development and manufacturing, may help gaining a deeper understanding of the freeze-drying process and of the formulation of lyophilized products. Through this scientific and risk-based approach the drying technique may be understood, controlled, and shortened. Simultaneously, the formulation may be optimized so as to obtain a freeze-dried product with predictable quality, enabling its use in accordance with the proposed objective.

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