key: cord-0872864-kd0nwaqj
authors: Deokar, Vaibhav; Sharma, Alok; Mody, Rustom; Subrahmanyam M, Volety
title: Comparison of strategies in development and manufacturing of low viscosity, ultra-high concentration formulation for IgG1 antibody
date: 2020-09-15
journal: J Pharm Sci
DOI: 10.1016/j.xphs.2020.09.014
sha: 1c3dbbc6bd4f721ff3a398711e51a2fdb8a66d8f
doc_id: 872864
cord_uid: kd0nwaqj

Monoclonal antibodies requiring higher doses for exerting therapeutic effect but having lower stability, are administered as dilute infusions, or as two (low concentration) injections both resulting in reduced patient compliance. Present research summarizes impact of manufacturing conditions on ultra-high concentration (≥150mg/mL) IgG1 formulation, which can be administered as one subcutaneous injection. IgG1 was concentrated to ∼200mg/mL using tangential flow filtration (TFF). Alternatively, spray dried (SPD) and spray freeze dried (SFD) IgG1, was reconstituted in 30%v/v propylene glycol to form ultra-high concentration (∼200 mg/mL) injectable formulation. Reconstituted, SPD and SFD IgG1 formulations, increased viscosity beyond an acceptable range for subcutaneous injections (<20 cP). Formulations developed by reconstitution of SPD IgG1, demonstrated increase in high and low molecular weight impurities, at accelerated and stressed conditions. Whereas, the stability data suggested reconstituted SFD IgG1 was comparable to control IgG1 formulation concentrated by TFF. Also, formulation of IgG1 diafiltered with proline using TFF, reduce viscosity from ∼21.9 cP to ∼11 cP at 25°C and had better stability. Thus, conventional TFF technique stands to be one of the preferred methods for manufacturing of ultra-high concentration IgG1 formulations. Additionally, SFD could be an alternative method for long term storage of IgG1 in a dry powder state.

Due to inherent specificity and potential therapeutic activity, monoclonal antibodies have proven to be one of the most efficient therapeutic agents in treatment of several life threatening disorders. 1, 2 By April 2020, about 84 different antibodies have been approved by European Medical Agency (EMA) and US FDA for various indications. However, majority of the approved antibodies require higher doses (>100 mg per dose) to demonstrate desired therapeutic effect. Some antibodies at higher concentrations can show limited stability in aqueous solutions, and are manufactured as lyophilized products which are further reconstituted, prior to administration as intravenous infusion (IV). 3,4 Lyophilization further increases manufacturing cost. At times, antibodies with larger dose and having poor stability at higher concentration, are injected as two injections at a time ( Table 1 ). All these circumstances together result in reduced patient compliance and adds to the cost of administration. 5, 6, 7 Refer Table 1 :

Recent advances in antibody therapeutics are mainly focused on development of high concentration antibody formulations (>100 mg/mL concentration) which can administer higher doses in smaller injection volumes.

Herceptin SC ® 600 mg (5 mL injection volume) and Rituxan ® SC 1600 mg (13.4 mL injection volume), are two such examples of recent developments in high concentration antibody formulations (at ~120 mg/mL), and require specialized pumps and auto-devices for subcutaneous delivery, increasing cost of administration. Thus, there is need to develop low viscosity, ultra-high concentration antibody formulations which are stable, cost effective and capable of self-administering larger doses as a single sub-cutaneous injection. 8 Antibodies approved in past 35 years for various indications like multiple myeloma, metastatic breast cancer, migraine, osteoporosis etc., having doses >100 mg and concentration ≥100 mg/mL, are summarized in figure 1.

These formulations are commercialized as liquid and/or lyophilized presentations. In recent years there has been lot of research on stabilization and viscosity behavior of high concentration antibody formulations. 10, 11 However, there is less research on challenges associated in manufacturing of ultrahigh concentration antibody formulations and head-to-head comparative evaluation of their manufacturing J o u r n a l P r e -p r o o f 4 methods. Challenges in manufacturing of such antibody formulations are mainly associated with increased viscosity, which exceeds the capabilities of existing manufacturing practices and parenteral delivery systems.

Although widely used, tangential flow filtration (TFF) system may have limitation of membrane fouling due to higher viscosity. Hence, alternative membrane geometry and methods to reduce viscosity should be evaluated.

Concentration step by TFF also results variation in excipient content (e.g., concentration of polysorbates, buffer and excipient offset etc.) which may impact the stability of concentrated antibody formulation. Hence, alternate strategies and manufacturing methods for ultra-high concentration should be evaluated. Shire 12 has discussed alternate strategies like lyophilization at high concentration and reconstitution to generate high concentration antibody formulation. High concentration antibody formulations using spray drying technique has been demonstrated by Ginkanga et al. 13 with stability for 3 months at 40°C in dry state. However, stability post reconstitution has not been discussed.

Present research is mainly focused on scalable manufacturing strategies to develop ultra-high concentration (>150 mg/mL), low viscosity (<20 cps) antibody formulation suitable for single subcutaneous administration, and provides comparative evaluation of their impact on chemical and structural stability of biosimilar IgG1. 2, 9 Antibody used in the study is a lyophilized biosimilar IgG1 molecule and its commercially available formulation variants are:

i. Lyophilized formulation of 440 mg dose at ~22 mg/mL concentration for IV administration.

ii. Aqueous formulation of 600 mg dose at ~120 mg/mL co-formulated with hyaluronidase and injection volume of ~5 mL for subcutaneous administered using auto device over a period of 5 minutes. Size exclusion chromatography (SE HPLC):

The high and low molecular weight impurities, were determined by SE HPLC analysis using a Yarra 3 µm SEC-3000 column of 300 mm x 7.8 mm dimensions (make: Phenomenex, USA, P/N:00H-4513-K0 ) in an isocratic mode. The column was equilibrated at 0.5 mL/min with mobile phase containing 80 mM sodium phosphate, pH 6.8 with 0.3 M sodium chloride at a column oven temperature of 25°C. IgG1 samples were diluted to 0.5 mg/mL using mobile phase and detected at 280 nm. The column load for this method was 25µg of IgG1. 

Circular dichroism (CD) measurements were recorded using CD spectrophotometer (make: Jasco, Japan; model J -1500). The far-UV CD spectra (195 to 260 nm) for ultra-high concentration IgG1 from different manufacturing process were collected at 20°C using a quartz cell of 0.1 cm path length and protein concentration of 0.2 mg/mL.

After accumulation of 3 scans at a scan rate of 1 nm per second, the scans were subsequently corrected by subtracting formulation buffer as blank. Secondary structural components were calculated by CDNN software using molecular mass of 148.4 kDa and total number of 1328 amino acids.

IgG1 was concentrated to ~200 mg/mL using Ultracel ® 30 kDa Pellicon ® 3 cassettes (Merck Millipore) having 'D screen' geometry. Preliminary experimentation on concentration of IgG1 using Pellicon Biomax ® (PES) 30 kDa

Membrane ('A screen' membrane) could achieve concentration only upto 100 to 120 mg/mL (data not included).

Ultracel ® 'D screen' cassettes was able to achieve higher viscosity and higher concentrations under existing processing limits and conditions conventionally used for Pellicon Biomax ® cassettes having 'A screen' geometry.

Polysorbates are normally added to final concentrated DS due their propensity to concentrate on TFF membranes. This can pose a risk of aggregate formation due to absence polysorbate during concentration step.

Also, preliminary experiments suggested that polysorbate 20 present in the IgG1 was concentrated during the concentration and diafiltration step when Biomax ® cassettes 'A screen' geometry was used. This increase in polysorbate 20 concentration would result in inconsistency with respect to TFF process and formulation composition. Hence, polysorbate 20 was removed by passing IgG1 through SDR Hyper D resin in flow through mode (supporting data figure 1 ). IgG1 thus obtained without polysorbate 20 was used for further concentration to ~200 mg/mL using TFF system with D screen cassette. Polysorbate 20 was added to IgG1 after concentration.

Alternatively, to address this challenge of polysorbate 20 concentration, surfactants like sodium deoxycholate can be evaluated while developing ultra-high concentration antibody formulations. According to Malarkani et al. 22 J o u r n a l P r e -p r o o f and Albani et al. 23 sodium deoxycholate does not concentrate during TFF and helps to prevent any aggregation due to shear during concentration/diafiltration step. Also, sodium deoxycholate is routinely used in pharmaceutical injections and vaccines. 24,25,26,27,28,29. Excipient concentration in final DS differs from initial formulation buffer during concentration and diafiltration of proteins. This is either due to volume of exclusion, preferential hydration or charge dependent Donnan membrane effect. Thus, it is necessary to quantify the excipient concentration after concentration or diafiltration step. IgG1 samples withdrawn at different concentration folds were analyzed for protein content and excipient content during concentration of IgG1. It was observed that trehalose content was unchanged during the concentration process, thus rejecting the volume of exclusion hypothesis. But histidine content significantly reduced as the IgG1 was concentrated to ~200 mg/mL (supporting data figure 2 ).

In this case, reduction of histidine content could be possible due to Donnan membrane effect, wherein the Stoner et al. 32 and Teerters et al. 33 it can be concluded that, histidine with isoelectric point of 7.6 will be positively charge at pH 6.0. IgG1 with isoelectric point of 8.7 will also have net positive charge at pH 6.0, thus resulting in electrostatic repulsion during diafiltration step. As a result of histidine expulsion in permeate, change in pH of concentrated IgG1 at ~200 mg/mL was observed to increase from 6.0 to 6.5. Thus, diafiltration of IgG1 followed by concentration step results in buffer offset. Hence, strategies like diafiltration with higher buffer strength to compensate for buffer off-set while targeting higher IgG1 concentration, or addition of required histidine, histidine-HCl after diafiltration, or performing concentration step at lower pH ~5.5 (by adding more histidine-HCl in initial stage) followed by diafiltration to achieve target pH of ~6.0 after diafiltration, needs to be evaluated. Alternatively, buffering agents like citrate, phosphate or combinations thereof, which are negatively charged at pH 6.0, should be considered while formulating such antibody formulations. The concentrated IgG1 thus obtained was analyzed for histidine content and required amount of histidine was added to achieve the J o u r n a l P r e -p r o o f target concentration. IgG1 DS from above process was further used for developing low viscosity IgG1 formulation at ~200 mg/mL, for subcutaneous administration.

Roberts et al. 34 reported that salts and amino acids, reduce viscosity of protein formulation based on their ionic strength. Also, they are generally regarded as safe in injectable and were screened to develop low viscosity formulation within acceptable range for subcutaneous injection (i.e. <20 cP). Salts screened as viscosity reducing agents were sodium chloride, ammonium chloride, calcium chloride, magnesium chloride. Whereas, amino acids screened during the study were L-arginine hydrochloride, glycine and proline. The concentration of these viscosity reducing agents was such that the resultant osmolality of solution would be within internal osmolality target range of ~300 ± 20 mOsmols/kg. About 13 mL IgG1 DS was buffer exchanged with formulation buffer containing viscosity modifiers, using a 10 kDa membrane. Further, these buffer exchanged formulations were filled in EZ Fill USP type 1 prefillable syringe (PFS) barrels (make: Nuova Ompi, Italy; P/N:7600001.7439) with Flurotech ® coated stopper (make:

West, P/N:9000001.6075) and were charged on stability.

The viscosity data clearly indicates that IgG1 formulations containing viscosity modifiers showed lower viscosity at 5°C and 25°C ( Figure 2 ) . Calcium chloride showed significant impact on viscosity IgG1 followed by proline and glycine. However, osmolality of formulation containing calcium chloride was too high (~380 mOsmols/kg) than the targeted isotonic range (300±20 mOsmols/kg). As concluded by Roberts et al. 34 Table 2 ). In order to optimize the formulation composition and to determine their interaction effects, a DoE study with Response Surface Methodology (RSM) considering Central

Composite Rotatable Design (CCRD) was performed using Design Expert ® Software (supporting data figure 4 and 5). Based on observations from DoE study, IgG1 formulation with proline was selected for further studies.

Dias et al. 35 demonstrated that tolerability of high volume subcutaneous injection of ~3.5 mL viscous placebo buffer (like a typical protein formulation), administered over 1 min was associated with more pain than a 1.2 mL bolus injection. The pain was lesser compared to bolus injection when the same viscous placebo buffer was administered over 10 min. Another study evaluating impact of viscosity of monoclonal antibody formulation, injection volume and injection flow rate on SC injection tolerance, Dias et al. 35 concluded that injection volume of up to 3 mL having viscosity up to 15-20 cP, are well tolerated without pain, when administered into the abdomen, within 10 seconds. 2 Also, for patients with normal dexterity, the limit of viscosity for SC administration is up to 20 cps. Thus, based on conclusions of Berteau et al. 2 and Dias et al. 35 there is a possibility that ~3.0 mL IgG1 at ~200mg/mL with proline having viscosity ~11-12 cP could be administered over a period of 5 to 10 min, with less pain. Prasetyono et al. 37 reported that, clinically the moment of pushing the piston sliding inside the Siew et al. 36 and ISO guidance 38 describe that injection of solution requires two types of forces as parameters of injectability, i.e. the initial force when piston of syringe is pushed; known as plunger-stopper 'break loose force' and the maintenance force required to keep pushing the piston in a sustained way; known as dynamic 'gliding force'. Both injections forces are affected by the diameter of needle and syringe, as well as viscosity of the solution. However, keeping the container closer system (prefilled syringe and needle) constant, the glide force and break loose force should be impacted by viscosity of the solution. It can be observed that IgG1 at 200mg/mL having viscosity >20 cP has glide force of ~9.5N and break loose force is 5.5N ( Table 2 ). Addition of viscosity modifiers resulted in viscosity below 20 cP with average break loose force of ~4.8N and an average glide force of ~3.3N, which can be considered as tolerable injection force with respect to pain perception.

Ginkanga B. et al. 13 demonstrated that manufacturing of high-concentration antibody formulations by spray drying has no process limitations with respect to concentration step. However, their study mainly focused on bulk storage of spray dried antibody and further formulation to high concentration drug product followed by stability in reconstituted state has not been evaluated. The spray drying (SPD) process involved spraying of IgG1 solution at high pressure through a heated nozzle (180°C) followed by drying in a chamber with a flow of hot air flow (80°C). Thus, the quality attributes of the antibody may get impacted during the drying process. An alternative to SPD, spray freeze drying (SFD) process which involves flash freezing of IgG1 in liquid nitrogen followed by bulk freeze drying can be explored. Faghihi et al. 39 and Yowa et al. 40 describe this process as more subtle for proteins and is commercially viable option, but less studied in manufacturing of high-concentration antibody formulations.

The spray dried powder of IgG1 had higher bulk density (was heavier) as compared to spray freeze dried IgG1 powder. Thus, SFD IgG may be difficult for handling during dispensing and compounding process, posing the risk of airborne cross contamination. Table 3 summarizes formulation composition of IgG1, total solids per mL of IgG1 and % recovery obtained from SPD and SFD processes. The recovery of IgG1 dry powder was higher J o u r n a l P r e -p r o o f (>90%) in case of SPD process as compared to (~85%) SFD process. Lower recovery observed in SFD process can be attributed to process loss in an open system as compared to spray drier which had closed system. Impact of SPD and SFD on the morphology of IgG1 is summarized in supporting data figure 3 and table 4 .

Wang et al. 41 , Srinivasan et al. 43 Also, the composition of spray dried and spray freeze dried IgG1 powder is identical and, reconstitution of IgG1 powder from SPD and SFD process in WFI would result in IgG1 at ~200mg/mL (without any viscosity modifier), but having higher viscosity ( Figure 2 ). Thus, with an anticipation to form colloidal suspension of IgG1, 30%v/v of PG was selected as an alternative vehicle for reconstitution of spray dried and spray freeze dried IgG1 for manufacturing of low viscosity, ultra-high concentration IgG1 formulation for intramuscular or subcutaneous administration.

The commercially available formulation variant of IgG1 has a dose of 600 mg for subcutaneous injection.

Preliminary experiments suggested that reconstitution of ~2 g of spray dried or spray freeze dried IgG1 powder into ~3.0 mL of WFI, resulted in IgG1 at ~200 mg/mL concentration. Thus, reconstitution of spray dried or spray freeze dried IgG1 powder into 3.0 mL of 30% v/v of PG would result in colloidal suspension at 200 mg/mL of IgG1 with a dose of 600 mg. The reconstitution time of SPD IgG1 in WFI and 30% PG was higher (supporting data table 2).

The IgG1 (200 mg/mL) with proline as viscosity modifier (manufactured by TFF) and IgG1 (200 mg/mL) reconstituted in 30% v/v PG in IgG1 formulation buffer (manufactured by SPD and SFD) were filled in 3.5 mL USP type 1 glass syringe having tamper evident OVS ® closure (make: Schott Kaisha, India; P/N: SB00303).

Spray dried and spray freeze dried IgG1, reconstituted in 30 %v/v of PG resulted in a clear but highly viscous solution, instead of a colloidal suspension. The viscosity of SFD sample was ~80 cps and that for SPD samples was ~93 cps when measured at 25°C.The solution of spray freeze dried IgG1 in 30% v/v of PG was almost colorless, while spray dried IgG1 in 30% v/v of PG had brownish discoloration. These formulations were charged on stability at real time (5°C), accelerated (25 °C ± 2°C/60% RH) and stress conditions (40°C ± 5°C/75% RH) along with IgG1 at 200 mg/mL (without any viscosity modifier and without 30% PG) as control sample and were compared for impact of manufacturing conditions on stability. Table 4 Impact of manufacturing conditions on conformational changes in secondary structure of IgG1 in ultra-high concentration formulations, was evaluated by analyzing formulations from different manufacturing techniques using far UV CD. Lyophilized IgG1 (reconstituted in WFI and having identical composition to SPD and SFD IgG1 powder) was used as additional control sample to compare structural changes due to processing.

Refer Table 4 :

The formulation composition of IgG1 used in SPD and SFD process is identical and head-to-head comparison between these two processes can be established after reconstitution in 30% PG. From table 4, it can be observed that, although the SPD and SFD formulations have identical composition, there is significant increase in % HMWs for formulation obtained from SPD process. Whereas formulation from SFD process is relatively stable and comparable to control sample (without 30% PG). It was observed that acidic and basic variants were not impacted by SPD and SFD conditions nor by adding 30% PG, and were comparable to TFF and control control. This could be because the pH of formulations, IgG1 SPD (pH=6.2) and IgG1 SFD (pH=6.1) (containing 30% PG) was within the target range of 6.0±0.3. The sub-visible particle analysis by flow imaging microscopy demonstrated marginally higher particles in IgG1 formulation from SPD process on reconstitution with 30% PG.

The particles form SPD process were dark as compared to other strategies and had mixed morphology of both round shaped and elongated particles (supporting data table 4). However, IgG1 formulation from SFD process had relatively lower sub-visible particles and were comparable to control formulation. As both IgG1 SPD and IgG1 SFD have identical composition, the rise in particulates in IgG1 SPD formulation can be attributed to processing conditions and not to the presence of 30% PG. Thus, it can be concluded that differences in quality attributes of SE HPLC and sub visible particulates are due to impact of processing conditions and presence of 30% PG does not have any impact on stability of ultra-high concentration IgG1.

Formulation from TFF additionally has proline, as viscosity reducing agent. It can be seen from the 6 month accelerated (25°C ± 2°C/60% RH) stability data ( CD spectra of control sample (IgG1 without proline and without PG) showed zero intensity at 206 nm, minimum intensity at 217 nm and a broad shoulder at ~228 nm which indicates presence of β-sheet as predominant structure (table 5) . These results were consistent with the structure reported for native IgG1 molecule by Pabari et al. 47 and Lee et al. 48 Refer Figure 3 :

Refer Table 5 :

Refer Table 6 :

IgG1DS from SPD, SFD and TFF, has wavelength at zero intensity, spectra minima and broad shoulder;

comparable with IgG1 controls (without proline and without PG and lyophilized IgG1) (figure 3 and table 5) .

Although there is increase in HMW impurities in SPD IgG1, but there is no co-relation with any change in the J o u r n a l P r e -p r o o f secondary structure. The secondary structure analysis summarized in table 6 confirmed that β-sheet was the predominant structure (48% β-sheet, 5.5% αhelix and 34% was random coil). As demonstrated by Schüle et al. 49 and Ng et al. 50 the variation in secondary structure of high concentration IgG1 from different manufacturing conditions was within the error of the measurement technique(i.e. 3 to 4 %) suggesting that there is no significant impact of difference in excipients and manufacturing conditions on secondary structure of ultra-high concentration IgG1. Therefore, IgG1 concentrated upto 200 mg/mL by different manufacturing techniques and having difference of excipients (proline in formulation from TFF and 30% PG in formulation from SPD and SFD) and manufacturing conditions (e.g., nozzle temperature of 180°C) does not lead to any change in the secondary structure of IgG1. This confirms that IgG1 remains chemically and conformationally intact when exposed to stresses of above mentioned manufacturing conditions.

A low viscosity ultra-high concentration IgG1 formulation at 200 mg/mL was successfully developed by using TFF process. The limitation of conventionally used 'A' Screen membrane to achieve maximum IgG1 concentration upto ~120 mg/mL was circumvented using 'D' screen membrane (Ultracel ® 30 kDa Pellicon ® 3). From the comparative evaluation of different methods, TFF stands to be the most preferred method for manufacturing of high concentration antibody formulation. This is followed by SFD which can be a potential method for manufacturing of bulk dried powders of IgG1 with no significant impact on purity.

manufacturing of low viscosity, ultra-high concentration formulation for IgG1 antibody. 

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Conformational analysis of protein secondary structure during spray-drying of antibody/mannitol formulations

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J o u r n a l P r e -p r o o f