Palbociclib Commercial Manufacturing Process Development. Part II

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Palbociclib Commercial Manufacturing Process Development. Part II: Regioselective Heck Coupling with Polymorph Control for Processability Mark Thomas Maloney, Brian P Jones, Mark A. Olivier, Javier Magano, Ke Wang, Nathan D. Ide, Andrew S. Palm, David R. Bill, Kyle R Leeman, Karen Sutherland, John Draper, Adrian Mark Daly, Joseph A. Keane, Denis Lynch, Marie O\'Brien, and Joanne Tuohy Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00069 • Publication Date (Web): 12 May 2016 Downloaded from http://pubs.acs.org on May 15, 2016

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Organic Process Research & Development

Palbociclib Commercial Manufacturing Process Development. Part II: Regioselective Heck Coupling with Polymorph Control for Processability Mark T. Maloney,1* Brian P. Jones,1 Mark A. Olivier,1 Javier Magano,1 Ke Wang,1 Nathan D. Ide,1† Andrew S. Palm,1 David R. Bill,1 Kyle R. Leeman,1 Karen Sutherland,1 John Draper,2 Adrian M. Daly,3 Joseph Keane3, Denis Lynch,3 Marie O’Brien,3 and Joanne Tuohy3 1

Pharmaceutical Sciences, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA, 2Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK, 3 Pfizer Global Supply, Ringaskiddy, Co.Cork, Ireland

ACS Paragon Plus Environment

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Table of Contents Graphic

Desaturation time vs. seed particle size (D90) Desaturation time, hrs

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8 6 4 2 0 0

50

100 150 D90, microns

200

250


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ABSTRACT: A three-step commercial manufacturing route has been developed for palbociclib, a highly selective, reversible inhibitor of CDK 4/6. The second step, which utilizes a Heck coupling to install the enol ether side chain, is described. A highly regioselective catalyst was identified for this transformation along with reaction conditions that ensure robustness upon scale-up. Effective removal of palladium was accomplished via filtration of insoluble metal and an extractive chelation step. Finally, efficient isolation of coupled product 3 was achieved through careful polymorph control via seeding and an optimized cooling protocol that avoids nucleation of a kinetically-favored, slow-filtering polymorph.

KEYWORDS: Heck coupling, oxygen-sensitive catalysis, polymorph control, seed particle size, cooling crystallization


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1 Introduction

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, involved in cellular progression from growth phase (G1) into the phase associated with DNA replication (S).1 Increased CDK 4/6 activity is frequently observed in estrogen receptor-positive (ER+) breast cancer.2 Palbociclib, 1, (Figure 1) is a highly selective, reversible inhibitor of CDK 4/6, intended to block tumor cell proliferation. Palbociclib received accelerated approval from the United States Food and Drug Administration (FDA) in February 2015. It is used in combination with letrozole, for the treatment of postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer as initial endocrine-based therapy. Palbociclib is marketed under the brand name IBRANCE®.

Figure 1. Structure of Palbociclib (1). The commercial manufacturing route for palbociclib, shown in Scheme 1, is documented in a series of three papers. While this route offers many improvements over the original discovery chemistry route, the discovery route established the current convergent synthetic strategy. Both the discovery and early clinical manufacturing routes to palbociclib are discussed in Part I of this series.3 This paper (Part II) focuses on the installation of the enol ether side-chain by Heck coupling to produce intermediate 3.


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The Heck reaction is a popular method of carbon-carbon bond formation between an aryl halide and an olefin. Like many palladium-catalyzed cross-coupling reactions, the Heck reaction can be oxygen sensitive. Regioselectivity in the reaction can be influenced by the choice of ligand, with alpha selectivity favored by bi-dentate ligands. 4 In this paper, we describe the development of a scalable process to manufacture compound 3. For the reaction, key challenges included selection of a catalyst/ligand system which provided high selectivity and identification of appropriate reaction conditions to ensure process robustness. For product isolation, we sought effective methods for palladium removal and controlling crystal morphology in order to enable efficient product filtration. Scheme 1. Commercial Manufacturing Process for Palbociclib Me Me Br

N Cl

Me Me

N

N

O

N

N

O Pd(OAc)2 DIPEA DPEPhos n-BuOH 95 °C (84%)

N Boc

Step 2

HN +

CyMgCl

NH2 N

THF 20 °C

Me Br

N

N

N

O

Step 1

N Boc

2

Me

N HN

Me

N N

N

O

HN HCl

N

n-BuOH Anisole H2O 70 °C (90%)

N

(88%) N

O

N Boc

Step 3

3

O N

N

O

N

N N H

1

2 Results and Discussion

2.1 Catalyst Selection Scheme 2. Heck Conditions for Early Clinical Supplies


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Me

Me Br

N

N

O N

HN

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N

N

O

.

PdCl2(dppf) CH2Cl2 LiOTf DIPEA

O N

HN

N

O

N

n-BuOH N N Boc

N 2

N Boc

3

Scheme 2 describes an optimized version of the Heck reaction developed to produce kg quantities of the penultimate intermediate 3 for early clinical supplies. Bromide 2 is slurried in n-butanol (6 vol) and treated with n-butyl vinyl ether (3 equiv), diisopropylethylamine (2.4 equiv), lithium triflate (1 equiv), and PdCl2(dppf)•dichloromethane adduct (0.04 equiv) at 95 °C under nitrogen. These conditions can be used to produce enol ether 3 in 75-82% isolated yield. However, several key impurities are also formed in the reaction that are difficult to purge. These impurities are shown in Scheme 3. While the lithium triflate additive was found to suppress formation of the impurities to a certain extent, typical lab scale reactions under these conditions still form 1% of the des-bromo impurity 4, 0.2 – 0.4% of the vinyl impurity 5, and 0.1 – 0.3% each of the regioisomer impurities 6 and 7.

Scheme 3. Key Impurities formed in Heck Reaction


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Due to the difficulty in purging these impurities down to acceptable levels via the crystallizations in this step and the subsequent API step, investigation of other catalysts in an effort to eliminate or minimize their formation was undertaken. The solvent system was not examined further since we had already developed and successfully scaled work-up and crystallization conditions using n-butanol/water. In an attempt to utilize non-precious metal catalysts,5,6 initial experiments examined four different commercially available nickel catalysts at 5% loading and two different bases (triethylamine and K3PO4), in n-butanol at 90 °C. None of the conditions screened resulted in any desired product. In fact, only unreacted starting material was observed. We also examined 18 different Pd/C catalysts (ligandless conditions)7 using three different organic bases (triethylamine, diisopropylethylamine, and dicyclohexylmethylamine), in n-butanol at 90 °C. Again, no desired product was formed under any of the conditions; instead, unreacted starting material and 5-33% of the des-bromo impurity 4 were observed. Next, a larger screen of fifty different ligands and five different bases using a 4% loading of palladium acetate, in n-butanol at 90 °C, was undertaken. No lithium triflate additive was used in this screen. The reactions were run on 50 mg scale and were set up in a glove box to prevent oxidation of the ligands by oxygen. After heating in a reactor block overnight, each reaction was analyzed by UPLC. Of the 250 reactions run, approximately 65 went to completion. However, only reactions with Xantphos, bis(2diphenylphosphinophenyl)ether (DPEPhos), (+/-) BINAP, 1,1'-Bis(di-i-propylphosphino)ferrocene (dippf), and 1,4 Bis(diphenylphosphino)butane (dppb) exhibited a purity profile that appeared promising (>90% desired product). Not surprisingly, all of these cleaner hits were from reactions using bi-dentate phosphine ligands.4 The conditions which provided the best purity profiles from the screen were then verified on 50 mg scale, with and without one equivalent of lithium triflate additive. Following analysis of the UPLC data, it was determined that when lithium triflate was employed, Xantphos with diisopropylethylamine, Xantphos with dicylohexylamine, and bis(2-diphenylphosphinophenyl)ether


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(DPEPhos) with dicyclohexylamine all provided good conversion to desired product with low impurity levels. When lithium triflate was not employed, the best conditions were DPEPhos with diisopropylethylamine.

In order to simplify the process and avoid the added cost of lithium triflate, we decided to pursue the DPEPhos/diisopropylethylamine combination. Two experiments were set up on ten gram scale using the conditions described in Scheme 4. Experiment one used a 4% (molar) loading of palladium acetate and a 4.8% (molar) loading of DPEPhos ligand and was complete by UPLC within 2.5 hours. Experiment two used a 2% loading of palladium acetate and a 2.4% loading of DPEPhos ligand and was complete within 3.5 hours. Both reactions used our standard conditions of 6 volumes of n-butanol, 2.4 equivalents of diisopropylethylamine, and 3 equivalents of n-butyl vinyl ether at 95 °C. To our delight, in both cases it was observed that upon reaction completion the vinyl impurity 5 and regioisomer impurities 6 and 7 were each below 0.05%, and des-bromo impurity 4 was present at less than 0.5%. Each reaction mixture was processed forward to isolated solids using conditions that had been developed for the previous catalyst system. The resulting isolated product 3 from both reactions was found to be of excellent quality (greater than 99.7% product by UPLC). No new impurities were observed. The isolated yields were 80 and 82%, respectively, which were comparable to the yields obtained using the other catalyst (PdCl2(dppf)). This new catalyst system was selected for further development.

Scheme 4. Heck Conditions for Commercial Route


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2.2 Reaction Parameter Optimization

With a more effective catalyst system identified, we began examination of the impact of process parameters on reaction performance. From the start, it was evident that elevated levels of 4, 5, 6, and 7 resulted if oxygen was not rigorously excluded from the reaction mixture. Presumably, oxygen reacts with DPEPhos to form phosphine oxides which results in lower alpha regioselectivity since the palladium is no longer ligated by a bi-dentate ligand.4 The des-bromo and vinyl impurities form when the catalytic cycle is interrupted, which is more likely to occur when oxidized ligand disassociates from palladium. In order to quantify the acceptable level of oxygen, we purged each experiment with nitrogen that had been spiked with specific levels of oxygen. For the initial set of experiments, the oxygen level was set at 3000 ppm while the other reaction parameters (shown in Table 1) were varied according to a fractional factorial design of experiments (DOE).

Effective purging was ensured for each reaction by

monitoring the headspace oxygen content with a Mettler Toledo InPro® 6800 oxygen probe. A recent investigation of a palladium-catalyzed C-N coupling8 indicated that direct measurement of the dissolved oxygen content is preferred, but the headspace oxygen level can be used to accurately predict oxygen in the reaction matrix under equilibrium conditions.


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Data analysis for these experiments indicated that the reaction temperature and Pd(OAc)2 loading have a statistically significant yet small impact on the formation of 4, while both reaction temperature and ligand/ Pd(OAc)2 ratio affect the formation of isomers 6 and 7. Reaction dilution, n-butyl vinyl ether stoichiometry, and diisopropylethylamine stoichiometry all were shown to have no impact on reaction performance, so these parameters were held constant at their midpoint values for subsequent experiments. Accurate quantitation of the vinyl impurity 5, via UPLC, was not available for this data set due to overlap with peaks related to ligand.

Reaction Process Parameter

Range Explored

Reaction Dilution

5.5 to 6.5 ml/g starting material

Reaction Temperature

85 to 105 °C

Pd(OAc)2 Stoichiometry

0.010 to 0.030 eq.

Ligand/ Pd(OAc)2 Ratio

1.05 to 1.35 mol/mol

n-Butyl Vinyl Ether Stoichiometry

2.0 to 4.0 eq.

Diisopropylethylamine Stoichiometry

1.8 to 3.0 eq.

Table 1. Reaction process parameters for 1st DOE (3000 ppm oxygen and no added water) We did not assess water sensitivity in this initial DOE because we did not expect that any of the reaction components would contain significant levels of water. After the fact, the starting material 2 was found to be a potential source of water, especially if hydrated magnesium salts are not effectively removed during its isolation, as was the case during early development. Subsequent process improvements explained in an earlier paper3 ensured low salts levels such that compound 2 could readily be dried to NMT 0.2% water. Nonetheless, we decided to explore the impact of water content on reaction performance. We found that reactions with as little as 0.75% water (wt.% based on input of


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2) produced 0.5% of 6 + 7, while the level of these impurities in experiments with no added water was typically below the limit of detection. Water has been shown to react with Pd(II) phosphine complexes to produce Pd(0) complexes and phosphine oxides.9,10,11 The oxidation of one phosphine in a bidentate phosphine ligand would effectively result in a monodentate ligand. Our reaction screening showed that bidentate ligands provided significantly better alpha regioselectivity than monodentate ligands. This likely explains why water and oxygen have similar detrimental effects on reaction selectivity. Based on the water sensitivity of the reaction , we repeated the reaction DOE while spiking each reaction with 0.6% water (wt.% based on input of 2); this is the maximum expected water level based on the target water content of NMT 0.20% for 2 and water specifications for the remaining reagents and solvent. This second DOE indicated that Pd(OAc)2 loading and ligand/ Pd(OAc)2 ratio have the strongest impact on impurity formation, with decreased levels of 6 and 7 seen with higher Pd(OAc)2 loading and higher ligand/ Pd(OAc)2 ratio. Our final DOE examined the impact of a higher oxygen level (5000 ppm in supply nitrogen) on reaction performance while varying reaction temperature, catalyst loading, and ligand/ Pd(OAc)2 ratio. The goal was to establish parameter ranges for operating in manufacturing facilities that do not have access to nitrogen with ultra-low oxygen levels. The measured responses for these experiments included the % desbromo 4, the % combined isomers 6 + 7, and the % vinyl impurity 5, whose quantitation was possible in this DOE via an improved analytical method. Statistical analysis from this DOE indicates that the level of desbromo impurity 4 increases with both higher reaction temperature and catalyst stoichiometry. However, the magnitude of these effects is rather small, as illustrated by the response surface in Figure 2. Catalyst stoichiometry, ligand/ Pd(OAc)2 ratio, and the interaction between these two parameters all have a statistically significant impact on the formation of the vinyl impurity 5 and the isomers 6 +7, though the impact on 5 is modest as shown in


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Figure 3. The sum of the isomers 6 + 7 is more sensitive to these parameters, with a significant increase in these impurities at low catalyst stoichiometry and ligand/ Pd(OAc)2 ratio as seen in Figure 4. Based on the output from this DOE and previous experimental results, parameter values were established to ensure high selectivity in formation of enol ether 3. These conditions have been executed successfully at full scale (80 to 180 kg input) for more than 40 consecutive batches, with excellent purity and levels of the vinyl impurity 5 and the isomers 6 and 7 5 hours for the slurry-treated seed and only 2.6 hours for dry seed. Further comparison of dry vs. slurry seeding was made by revisiting results from several experiments where isolated 3 was recrystallized from n-butanol/water using conditions similar to those of the standard product crystallization. Two experiments with slurry seeding that had produced significant levels of Form A (due to an excessive cooling rate) were repeated with dry seeding, These experiments produced no Form A crystals, supporting the hypothesis that the desaturation rate is faster with dry seeding, however the Form C crystals were smaller than those seen in standard slurry seeding experiments. Likewise, a comparison of product lots made in the laboratory (Figure 15) illustrates that crystals obtained from slurry seeding are significantly larger than those obtained with dry seeding. Even though the crystals obtained from dry seeding are typically much smaller, they still filter quickly and do not present any processing difficulties at full scale.


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100 microns 100 microns

Figure 15. Comparison of crystals obtained in the laboratory from slurry seeding (left) and dry seeding (right).

2.4.3 Crystallization Cooling Protocol To allow for adequate desaturation time during crystallization, and therefore minimize risk of Form A nucleation, a staged cooling protocol was established for the laboratory and pilot plant. The original protocol, shown in Figure 16, provided the desired polymorph (Form C) exclusively for most pilot plant lots, though some Form A nucleation was seen towards the end of the cooling ramp in a few batches. This nucleation is easily detected via FBRM as a sudden increase in the number of particles in all size bins, as shown in Figure 17, and is clearly evident via light microscopy due to the difference in crystal habit between the two polymorphs. Fortunately, when Form A crystals are detected, they can readily be converted to Form C crystals by slow heating to 35 °C, followed by controlled cooling back to 20 °C.


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Cool to 60C, seed, hold 90 minutes

Cool to 50C over 1 hr, hold 3 hrs

Cool to 30C over 3 hrs, hold 2 hrs

Cool to 20C over 4 hrs, hold 4 hrs Figure 16. Initial pilot plant protocol for Form C crystallization

Form A nucleation

Figure 17. Form A nucleation detected by FBRM in pilot plant lot.


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In order to design a cooling protocol that more effectively avoids Form A nucleation, the dynamic crystallization kinetics were studied using concentration feedback control. An automated reactor, equipped with mid-IR and FBRM probes, was initially used to simultaneously measure both a solubility curve for Form C and to collect IR spectra across a range of solute concentrations and temperatures. The mid-IR spectral data, together with corresponding temperature data, were subsequently used to build a chemometric calibration model which could accurately predict the solution concentration of 3. Experiments were then executed where a target supersaturation was set, relative to the Form C solubility, and a model predictive controller maintained the supersaturation setpoint by dynamically adjusting the cooling rate based on concentration measured by the mid-IR calibration model. Figure 18 compares the concentration profile obtained from the stepwise cooling profile in Figure 16 with the profile obtained using supersaturation control. It is clear from these curves that the profile derived by supersaturation control keeps the process undersaturated in Form A and thus greatly reduces the likelihood of the crystallization of Form A. A comparison of the temperature-time profiles for the two cooling protocols is given in Figure 19, along with a third, simplified temperature profile that approximates the feedback control protocol using two linear cooling ramps. This simplified protocol can be readily implemented at all manufacturing sites while mimicking the more favorable crystallization conditions determined through concentration feedback control.


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Figure 18: Comparison of the process supersaturation trajectory obtained from the stepwise protocol (orange) from Fig 16 and that obtained using concentration control (blue). Dotted lines indicate the solubility curves for Forms A and C.


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Time - Temperature Profiles 70

Protocol from Figure 17 Feedback Control

60

Temperature (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Approximation with Linear Ramps

50 40 30 20 10 0:00:00

4:00:00

8:00:00

12:00:00

16:00:00

20:00:00

24:00:00

Time since Seeding (hours)

Figure 19. Comparison of three cooling time-temperature profiles: the initial protocol shown in Figure 16 (green); a protocol executed using concentration feedback control (red); and an approximation of the feedback control protocol using two linear ramps (dotted line). In order to design experiments to define the manufacturing operating parameter ranges for the crystallization, we adopted a cooling protocol based on the two linear ramps (dotted line) shown in Figure 19. The data in Figure 19 suggest that the first cooling ramp should be from 60 to 35 °C and the second from 35 to 20 °C. However, we chose to set the transition between the two ramps at 30 °C based on the fact that essentially all instances of Form A nucleation had been seen below 30 °C. This choice allowed us to apply moderate cooling above 30 °C and very slow cooling below 30 °C in order to suppress Form A nucleation while minimizing the total cycle time. A fractional factorial experimental design was executed to examine the cooling rate for the two temperature ramps along with the seed loading. A cooling rate of 2.5 to 8°C/hr was investigated for the


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initial cooling ramp and 0.8 to 4°C/hr for the cooling ramp to 20°C, while the seed loading was varied from 0.0025 to 0.010 kg/kg of compound 2. From these experiments, a preferred crystallization protocol was chosen, which has been executed dozens of times at both pilot plant and manufacturingscale without any detectable formation of Form A crystals.

Conclusions

An efficient process has been developed for the second step of the palbociclib commercial manufacturing route, a Heck coupling to install the enol ether side chain. An extensive screen led to a highly regioselective catalyst system (Pd(OAc)2/DPEPhos), while further studies established robust reaction conditions. The reaction selectivity was found to be sensitive to both oxygen and water, though clean conversion was demonstrated for realistic manufacturing conditions (5000 ppm oxygen in supply nitrogen and 0.6 wt.% water on a starting material basis). Residual palladium was effectively removed through a combination of filtration and extractive chelation procedures. Careful study of the polymorph landscape, seeding behavior, and crystallization kinetics led to consistent isolation of the thermodynamically-preferred, fast-filtering crystal Form C. The complete process has been scaled successfully dozens of times at both pilot plant and manufacturing scales.

Experimental Section

Reactions were monitored by reverse phase UPLC. UPLC conditions: BEH Shield RP18, 2.1 x 100 mm, 1.7 µm, 45 °C, flow 0.4 mL/min; λ = 295 nm, 3 μL injection volume; A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile. Gradient 5% B to 95% B in 8 minutes, re-equilibrate to 5% B in 0.1 min. Diluent: 50:25:25 tetrahydrofuran:acetonitrile:purified water.


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NMR data were collected using a Bruker AV III 600MHz spectrometer with TCI cryoprobe. HRMS data was obtained using a Thermo Orbitrap XL using Electrospray Ionization in positive mode.

tert-butyl 4-(6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2ylamino)pyridin-3-yl)piperazine-1-carboxylate (3). To a dry, nitrogen-purged reactor was added nbutanol (60 ml, 6 vol), 2 (10 g, 17.1 mmol, 1 equiv), n-butyl vinyl ether (5.1 g, 51.3 mol, 3.0 equiv), and diisopropylethylamine (5.3 g, 41.1 mmol, 2.4 equiv). The system was inerted and palladium acetate (0.078 g, 0.34 mmol, 0.02 equiv) and bis(2-diphenylphosphinophenyl)ether (0.235 kg, 0.43 mmol, 0.025 equiv) were added. The mixture was heated to 85 °C and stirred overnight. Upon reaction completion the mixture was cooled to 80 °C and water (15 ml, 1.5 vol) and n-butanol (30 ml, 3 vol) were added. The solution was passed through a filter cartridge then water (35 ml, 3.5 vol) and 1,2-diaminopropane (3.8 g, 51.3 mmol, 3.0 equiv) were added. The aqueous phase was removed and the organic phase was cooled to 60 °C and then seeded with 3 (50 mg, 0.005 kg/kg). The slurry was cooled slowly to 20 °C. The solids were filtered and washed twice with n-butanol (20 ml, 2 vol) and three times with methyl t-butyl ether (20 ml, 2 vol) then dried at 70 °C to give 8.8 g (85% yield) of 3. 1

H NMR (600 MHz, DMSO-d6): 10.0 (s, 1H), 8.87 (s, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H),

7.48 (dd, J = 9.0, 2.9 Hz, 1H), 5.83 (m, 1H), 4.47 (d, J = 1.6 Hz, 1H), 4.05 (d, J = 1.6 Hz, 1H), 3.77 (t, J = 6.4 Hz, 2H), 3.48 (broad, 4H), 3.11 (broad, 4H), 2.37 (s, 3H), 2.22 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H), 1.58 (m, 2H), 1.43 (s, 9H), 1.38 (m, 2H), 0.90 (t, J = 7.39 Hz, 3H); 13C NMR (150 MHz, DMSO-d6): 160.9, 158.2, 157.3, 155.2, 154.6, 153.7, 145.0, 143.0, 142.6, 136.0, 125.8, 125.5, 114.6, 106.6, 87.8, 78.9, 66.8, 52.8, 48.5, 43.4, 42.5, 30.3, 28.0, 27.4, 25.1, 18.8, 14.4, 13.6; HRMS: Calcd for C33H46N7O4 (M+H)+: 604.3606, Found: 604.3605.

Instrumentation/Analysis ReactIR and FBRM probes are from Mettler Toledo Autochem Inc., Columbia, MD, USA.


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Raman instrument and probes are from Kaiser Optical Systems Inc., Ann Arbor, Michigan, USA Chemometric modeling and model predictive control were executed using PharmaMV software from Perceptive Engineering Ltd., Daresbury, UK.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Present Address †

Abbvie, Inc., 1400 Sheridan Road, North Chicago, IL 60064

Funding Sources The authors declare no competing financial interest. ACKNOWLEDGMENT We gratefully acknowledge the contributions of the Pfizer PDF operation staff and Pfizer PGS Ringaskiddy operation staff for their support during clinical and commercial manufacturing. We also acknowledge the important contributions from our Process Safety Group.

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Palbociclib Commercial Manufacturing Process Development. Part II

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