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SUPAC: Manufacturing Equipment Addendum

Guidance for Industry

U.S. Department of Health and Human ServicesFood and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 2014Pharmaceutical Quality/CMC



SUPAC: Manufacturing Equipment Addendum

Guidance for Industry

Additional copies are available from:Office of Communications, Division of Drug Information

Center for Drug Evaluation and ResearchFood and Drug Administration

10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993

Phone: 855-543-3784 or 301-796-3400; Fax: [email protected]

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human ServicesFood and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 2014Pharmaceutical Quality/CMC



Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. DISCUSSION .................................................................................................................... 2

IV. SUPAC IR/MR INFORMATION.................................................................................... 3

A. Particle Size Reduction/Separation .............................................................................................. 3

1. Definitions........................................................................................................................................ 3 2. Equipment Classifications ............................................................................................................... 4

B. Blending and Mixing...................................................................................................................... 6

1. Definitions........................................................................................................................................ 6 2. Equipment Classifications ............................................................................................................... 6

C. Granulation .................................................................................................................................... 7

1. Definitions........................................................................................................................................ 7 2. Equipment Classification ................................................................................................................. 9

D. Drying ........................................................................................................................................... 11

1. Definitions ...................................................................................................................................... 11 2. Equipment Classifications ............................................................................................................. 13

E. Unit Dosing ................................................................................................................................... 14


F. Soft Gelatin Capsule .................................................................................................................... 16


G. Coating/Printing/Drilling ............................................................................................................ 19

1. Definitions ...................................................................................................................................... 19 2. Equipment Classification ............................................................................................................... 22

V. SUPAC-SS INFORMATION......................................................................................... 24

A. Particle Size Reduction/Separation ............................................................................................ 24

B. Mixing ........................................................................................................................................... 24

1. Definitions...................................................................................................................................... 24 2. Equipment Classification............................................................................................................... 25

C. Emulsification............................................................................................................................... 25

1. Definitions...................................................................................................................................... 25




2. Equipment Classification............................................................................................................... 26

D. Deaeration..................................................................................................................................... 26


E. Transfer ........................................................................................................................................ 27

1. Definition ....................................................................................................................................... 27 2. Equipment Classification............................................................................................................... 27

F. Packaging...................................................................................................................................... 28





1

Guidance for Industry11SUPAC: Manufacturing Equipment Addendum2

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4This guidance represents the Food and Drug Administration’s (FDA’s or Agency’s) current thinking on 5this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA 6or the public. You can use an alternative approach if the approach satisfies the requirements of the 7applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff 8responsible for implementing this guidance using the contact information on the title page of this 9guidance. 10

11

121314

I. INTRODUCTION 1516

This guidance combines and supersedes the following scale-up and post-approval changes17(SUPAC) guidances for industry: (1) SUPAC-IR/MR: Immediate Release and Modified 18Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum, and (2) SUPAC-SS 19Nonsterile Semisolid Dosage Forms, Manufacturing Equipment Addendum.2 It removes the lists 20of manufacturing equipment that were in both guidances and clarifies the types of processes being 21referenced.22

23A draft guidance, SUPAC: Manufacturing Equipment Addendum, was published on April 1, 2013.24Comments were received and changes were made to address those comments. 25

26This SUPAC addendum should be used in conjunction with the following SUPAC guidances for 27industry:3 (1) Immediate Release Solid Oral Dosage Forms — Scale-Up and Post-Approval28Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo29Bioequivalence Documentation, (2) SUPAC-MR: Modified Release Solid Oral Dosage Forms30Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro31Dissolution Testing and In Vivo Bioequivalence Documentation, and (3) SUPAC-SS: Nonsterile 32Semisolid Dosage Forms, Scale-Up and Post Approval Changes: Chemistry Manufacturing and33Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation.434

35The SUPAC guidances define: (1) levels of chemistry, manufacturing, and control change; (2)36recommended chemistry, manufacturing, and controls tests for each level of change; (3)37recommended in vitro dissolution and release tests and/or in vivo bioequivalence tests for each38

1 This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 2 For this guidance only, the new document that is a combination of these two guidances will be referred to as the SUPAC addendum.3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.4 For this guidance only, this collective group of guidances will be referred to as SUPAC guidances.




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level of change; and (4) recommended documentation that should support the change for new39drug applications and abbreviated new drug applications.40

41This SUPAC addendum, together with the SUPAC guidances, is intended to help you, the 42manufacturer, determine the documentation you should submit to FDA regarding manufacturing 43equipment changes.44

45FDA’s guidance documents, including this guidance, do not establish legally enforceable 46responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 47be viewed only as recommendations, unless specific regulatory or statutory requirements are 48cited. The use of the word should in Agency guidances means that something is suggested or 49recommended, but not required. 50

51II. BACKGROUND52

53When the SUPAC equipment addenda were published with tables referencing specific 54equipment, the tables were misinterpreted as equipment required by FDA. FDA recognizes 55that scientific innovation and technology advancement are commonplace and play a significant 56role in pharmaceutical development, manufacturing, and quality assurance, and we are57concerned that such a misunderstanding could discourage advancements in manufacturing 58technologies. Therefore, this revised SUPAC addendum contains general information on59SUPAC equipment and no longer includes tables referencing specific equipment. This 60guidance also includes changes to clarify the types of processes being referenced.61

62III. DISCUSSION63

64The information in this guidance is presented in broad categories of unit operation. For 65immediate or modified release solid oral dosage forms, broad categories include blending and66mixing, drying, particle size reduction/separation, granulation, unit dosage, coating and printing,67and soft gelatin capsule encapsulation. For nonsterile semisolid dosage forms, broad categories 68include particle size reduction and/or separation, mixing, emulsification, deaeration, transfer, and 69packaging. Definitions and classifications are provided. For each operation, equipment is70categorized by class (operating principle) and subclass (design characteristic). Examples of types 71of equipment, but not specific brand information, are given within the subclasses.72

73When assessing manufacturing equipment changes from one class to another or from one 74subclass to another, you can follow a risk-based approach that includes a rationale and complies 75with the regulations, including the CGMP regulations.5, 6 We also recommend addressing the 76impact on the product quality attributes of equipment variations (via process parameters) when 77designing and developing the manufacturing process.778

79

5 21 CFR 314.70.6 21 CFR 210-211.7 L. X. Yu, G. Amidon, M. A. Khan, S. W. Hoag, J. Polli, G. K. Raju, and J. Woodcock, Understanding Pharmaceutical Quality by Design. The AAPS Journal. March 2014.




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When making equipment changes, you will need to determine the filing requirement.8 The 80SUPAC guidances provide information on how to do so. FDA will assess the changes based on 81the types of equipment changes being considered. If you choose an approach that exceeds the 82SUPAC guidances and addendum, FDA will assess the changes provided they are supported by 83a suitable risk-based assessment.84

85At the time of the equipment change, you should have available the scientific data and rationale86used to determine the type of change and documentation required. This information is subject to87FDA review at its discretion.88

89IV. SUPAC IR/MR INFORMATION90

91A. Particle Size Reduction/Separation92

931. Definitions94

95a. Unit Operations96

97i. Particle Size Reduction: The mechanical process of breaking particles into98

smaller pieces via one or more particle size reduction mechanisms. The99mechanical process used generally is referred to as milling.100

101a. Particle – Refers to either a discrete particle or a grouping of particles, 102

generally known as an agglomerate.103104

b. Particle Size Reduction Mechanisms105106

• Impact - Particle size reduction by applying an 107instantaneous force perpendicular to the 108particle/agglomerate surface. The force can result from109particle-to-particle or particle-to-mill surface collision.110

111• Attrition - Particle size reduction by applying a force in a112

direction parallel to the particle surface.113114

• Compression - Particle size reduction by applying a force115slowly (as compared to Impact) to the particle surface in a116direction toward the center of the particle.117

118• Cutting - Particle size reduction by applying a 119

shearing force to a material.120121

ii. Particle Separation: Particle size classification according to particle size122alone.123

124

8 21 CFR 314.70.




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b. Operating Principles125126

i. Fluid Energy Milling127128

Particles are reduced in size as a result of high-speed particle-to-particle129impact and/or attrition; also known as micronizing.130

131ii. Impact Milling132

133Particles are reduced in size by high-speed mechanical impact or impact134with other particles; also known as milling, pulverizing, or comminuting.135

136iii. Cutting137

138Particles are reduced in size by mechanical shearing.139

140iv. Compression Milling141

142Particles are reduced in size by compression stress and shear between143two surfaces.144

145v. Screening146

147Particles are reduced in size by mechanically induced attrition through a 148screen. This process commonly is referred to as milling or149deagglomeration.150

151vi. Tumble Milling152

153Particles are reduced in size by attrition utilizing grinding media.154

155vii. Separating156

157Particles are segregated based upon particle size alone and without any158significant particle size reduction. This process commonly is referred to as159screening or bolting.160

1612. Equipment Classifications162

163a. Fluid Energy Mills164

165Fluid energy mill subclasses have no moving parts and primarily are distinguished166from one another by the configuration and/or shape of their chambers, nozzles,167and classifiers.168

169• Tangential Jet170• Loop/Oval171




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• Opposed Jet172• Opposed Jet with Dynamic Classifier173• Fluidized Bed174• Fixed Target175• Moving Target176• High Pressure Homogenizer177

178b. Impact Mills179

180Impact mill subclasses primarily are distinguished from one another by the 181configuration of the grinding heads, chamber grinding liners (if any), and 182classifiers.183

184• Hammer Air Swept185• Hammer Conventional186• Pin/Disc187• Cage188

189c. Cutting Mills190

191Although cutting mills may differ from one another in whether the knives are192movable or fixed and in the classifier configuration, no cutting mill subclasses193have been identified.194

195d. Compression Mills196

197Although compression mills may differ from one another in whether one or both198surfaces are moving, no compression mill subclasses have been identified.199

200e. Screening Mills201

202Screening mill subclasses primarily are distinguished from one another by the203rotating element.204

205• Rotating Impeller206• Rotating Screen207• Oscillating Bar208

209f. Tumbling Mills210

211Tumbling mill subclasses primarily are distinguished from one another by the212grinding media used and by whether the mill is vibrated.213

214• Ball Media215• Rod Media216• Vibrating217




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218g. Separators219

220Separator subclasses primarily are distinguished from one another by the 221mechanical means used to induce particle movement.222

223• Vibratory/Shaker224• Centrifugal225

226B. Blending and Mixing227

2281. Definitions229


232Blending and Mixing: The reorientation of particles relative to one another in233order to achieve uniformity.234

235b. Operating Principles236

237i. Diffusion Blending (Tumble)238

239Particles are reoriented in relation to one another when they are 240placed in random motion and interparticular friction is reduced241as the result of bed expansion (usually within a rotating242container); also known as tumble blending.243

244ii. Convection Mixing245

246Particles are reoriented in relation to one another as a result247of mechanical movement; also known as paddle or plow248mixing.249

250iii. Pneumatic Mixing251

252Particles are reoriented in relation to one another as a result of253the expansion of a powder bed by gas.254


257a. Diffusion Mixers (Tumble)258

259Diffusion mixer subclasses primarily are distinguished by geometric shape and260the positioning of the axis of rotation.261

262• V-blenders263• Double Cone Blenders264




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• Slant Cone Blenders265• Cube Blenders266• Bin Blenders267• Horizontal/Vertical/Drum Blenders268• Static Continuous Blenders269• Dynamic Continuous Blenders270

271b. Convection Mixers272

273Convection blender subclasses primarily are distinguished by vessel shape and274impeller geometry.275

276• Ribbon Blenders277• Orbiting Screw Blenders278• Planetary Blenders279• Forberg Blenders280• Horizontal Double Arm Blenders281• Horizontal High Intensity Mixers282• Vertical High Intensity Mixers283• Diffusion Mixers (Tumble) with Intensifier/Agitator284

285c. Pneumatic Mixers286

287Although pneumatic mixers may differ from one another in vessel geometry, air288nozzle type, and air nozzle configuration, no pneumatic mixer subclasses have 289been identified.290

291292

C. Granulation293294


a. Unit Operations297298

Granulation: The process of creating granules. The powder morphology is 299modified through the use of either a liquid that causes particles to bind through300capillary forces or dry compaction forces. The process will result in one or more301of the following powder properties: enhanced flow; increased compressibility;302densification; alteration of physical appearance to more spherical, uniform, or303larger particles; and/or enhanced hydrophilic surface properties.304


307i. Dry Granulation308

309




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Dry powder densification and/or agglomeration by direct310physical compaction.311

312ii. Wet High-Shear Granulation313

314Powder densification and/or agglomeration by the incorporation315of a granulation fluid into the powder with high-power-per-unit316mass, through rotating high-shear forces.317

318iii. Wet Low-Shear Granulation319

320Powder densification and/or agglomeration by the incorporation321of a granulation fluid into the powder with low-power-per-unit322mass, through rotating low-shear forces.323

324iv. Low-Shear Tumble Granulation325

326Powder densification and/or agglomeration by the incorporation327of a granulation fluid into the powder with low-power-per-unit328mass, through rotation of the container vessel and/or intensifier329bar.330

331v. Extrusion Granulation332

333Plasticization of solids or wetted mass of solids and334granulation fluid with linear shear through a sized orifice using335a pressure gradient.336

337vi. Rotary Granulation338

339Spheronization, agglomeration, and/or densification of a wetted or 340non-wetted powder or extruded material. This is accomplished by 341centrifugal or rotational forces from a central rotating disk, rotating 342walls, or both. The process may include the incorporation and/or 343drying of a granulation fluid.344

345vii. Fluid Bed Granulation346

347Powder densification and/or agglomeration with little or no shear 348by direct granulation fluid atomization and impingement on349solids, while suspended by a controlled gas stream, with350simultaneous drying.351

352viii. Spray Dry Granulation353

354




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A pumpable granulating liquid containing solids (in solution or 355suspension) is atomized in a drying chamber and rapidly dried by a 356controlled gas stream, producing a dry powder.357

358ix. Hot-melt Granulation359

360An agglomeration process that utilizes a molten liquid as a 361binder(s) or granulation matrix in which the active 362pharmaceutical ingredient (API) is mixed and then cooled down 363followed by milling into powder. This is usually accomplished 364in a temperature controlled jacketed high shear granulating tank 365or using a heated nozzle that sprays the molten binders(s) onto 366the fluidizing bed of the API and other inactive ingredients. 367

368x. Melt Extrusion369

370A process that involves melting and mixing API and an excipient 371(generally a polymer) using low or high shear kneading screws 372followed by cooling and then milling into granules. Thermal 373energy for melting is usually supplied by the electric/water heater 374placed on the barrel. Materials are either premixed or fed into an 375extruder separately. Melt extruder subclasses primarily are 376distinguished by the configuration of the screw.377

378• Single screw extruder379• Twin screw extruder 380

3812. Equipment Classification382

383a. Dry Granulator384

385Dry granulator subclasses primarily are distinguished by the densification force386application mechanism.387

388• Slugging389• Roller Compaction390

391b. Wet High-Shear Granulator392

393Wet high-shear granulator subclasses primarily are distinguished by the 394geometric positioning of the primary impellers; impellers can be top, bottom,395or side driven.396

397• Vertical (Top or Bottom Driven)398• Horizontal (Side Driven)399

400




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c. Wet Low-Shear Granulator401402

Wet low-shear granulator subclasses primarily are distinguished by the 403geometry and design of the shear inducing components; shear can be induced404by rotating impeller, reciprocal kneading action, or convection screw action.405

406• Planetary407• Kneading408• Screw409

410d. Low-Shear Tumble Granulator411

412Although low-shear tumble granulators may differ from one another in vessel413geometry and type of dispersion or intensifier bar, no low-shear tumble414granulator subclasses have been identified. 415

416• Slant cone417• Double cone418• V-blender419

420e. Extrusion Granulator421

422Extrusion granulator subclasses primarily are distinguished by the 423orientation of extrusion surfaces and driving pressure production 424mechanism.425

426• Radial or Basket427• Axial428• Ram429• Roller, Gear, or Pelletizer430

431f. Rotary Granulator432

433Rotary granulator subclasses primarily are distinguished by their structural 434architecture. They have either open top architecture, such as a vertical centrifugal435spheronizer, or closed top architecture, such as a closed top fluid bed dryer.436

437• Open438• Closed439

440g. Fluid Bed Granulator441

442Although fluid bed granulators may differ from one another in geometry, 443operating pressures, and other conditions, no fluid bed granulator subclasses444have been identified.445

446




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h. Spray Dry Granulator447448

Although spray dry granulators may differ from one another in geometry, 449operating pressures, and other conditions, no spray dry granulator subclasses have450been identified.451

452i. Hot-melt Granulator453

454Although, hot-melt granulator may differ from one another in primarily melting the 455inactive ingredient (particularly the binder or other polymeric matrices), no 456subclasses have been identified at this time.457

458Note:459If a single piece of equipment is capable of performing multiple discrete unit operations (mixing, 460granulating, drying), the unit was evaluated solely for its ability to granulate. If multifunctional 461units were incapable of discrete steps (fluid bed granulator/drier), the unit was evaluated as an462integrated unit.463

464D. Drying465


468a. Unit Operation469

470Drying: The removal of a liquid from a solid by evaporation.471


474i. Direct Heating, Static Solids Bed475

476Heat transfer is accomplished by direct contact between the wet 477solids and hot gases. The vaporized liquid is carried away by the 478drying gases. There is no relative motion among solid particles.479The solids bed exists as a dense bed, with the particles resting upon 480one another.481

482ii. Direct Heating, Moving Solids Bed483

484Heat transfer is accomplished by direct contact between the wet 485solids and hot gases. The vaporized liquid is carried away by the 486drying gases. Solids motion is achieved by either mechanical 487agitation or gravity force, which slightly expands the bed enough to 488flow one particle over another.489

490iii. Direct Heating, Fluidized Solids Bed491

492




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Heat transfer is accomplished by direct contact between the wet 493solids and hot gases. The vaporized liquid is carried away by the 494drying gases. The solids are in an expanded condition, with the 495particles supported by drag forces caused by the gas phase. The 496solids and gases intermix and behave like a boiling liquid. This 497process commonly is referred to as fluid bed drying.498

499iv. Direct Heating, Dilute Solids Bed, Spray Drying500

501Heat transfer is accomplished by direct contact between a highly 502dispersed liquid and hot gases. The feed liquid may be a solution, 503slurry, emulsion, gel or paste, provided it is pumpable and capable 504of being atomized. The fluid is dispersed as fine droplets into a 505moving stream of hot gases, where they evaporate rapidly before 506reaching the wall of the drying chamber. The vaporized liquid is507carried away by the drying gases. The solids are fully expanded508and so widely separated that they exert essentially no influence on509one another.510

511v. Direct Heating, Dilute Solids Bed, Flash Drying512

513Heat transfer is accomplished by direct contact between wet solids 514and hot gases. The solid mass is suspended in a finely divided state 515in a high-velocity and high-temperature gas stream. The vaporized 516liquid is carried away by the drying gases.517

518vi. Indirect Conduction, Moving Solids Bed519

520Heat transfer to the wet solid is through a retaining wall. The 521vaporized liquid is removed independently from the heating 522medium. Solids motion is achieved by either mechanical agitation523or gravity force, which slightly expands the bed enough to flow one 524particle over another.525

526vii. Indirect Conduction, Static Solids Bed527

528Heat transfer to the wet solid is through a retaining wall. The 529vaporized liquid is removed independently from the heating 530medium. There is no relative motion among solid particles. The 531solids bed exists as a dense bed, with the particles resting upon one 532another.533

534viii. Indirect Conduction, Lyophilization535

536Drying in which the water vapor sublimes from the product after 537freezing.538




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539ix. Gas Stripping540

541Heat transfer is a combination of direct and indirect heating. The 542solids motion is achieved by agitation and the bed is partially 543fluidized.544

545x. Indirect Radiant, Moving Solids Bed546

547Heat transfer is accomplished with varying wavelengths of energy. 548Vaporized liquid is removed independently from the solids bed. 549The solids motion is achieved by mechanical agitation, which550slightly expands the bed enough to flow one particle over one 551another. This process commonly is referred to as microwave 552drying.553


556a. Direct Heating, Static Solids Bed557

558Static solids bed subclasses primarily are distinguished by the method of 559moving the solids into the dryer.560

561• Tray and Truck562• Belt563

564b. Direct Heating, Moving Solids Bed565

566Moving solids bed subclasses primarily are distinguished by the method or 567technology for moving the solids bed.568

569• Rotating Tray570• Horizontal Vibrating Conveyor571

572c. Direct Heating, Fluidized Solids Bed (Fluid Bed Dryer)573

574Although fluid bed dryers may differ from one another in geometry, operating575pressures, and other conditions, no fluidized solids bed dryer subclasses have576been identified.577

578d. Direct Heating, Dilute Solids Bed, Spray Dryer579

580Although spray dryers may differ from one another in geometry, operating 581pressures, and other conditions, no spray dryer subclasses have been identified.582

583




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e. Direct Heating, Dilute Solids Bed, Flash Dryer584585

Although flash dryers may differ from one another in geometry, operating 586pressures, and other conditions, no flash dryer subclasses have been identified.587

588f. Indirect Conduction Heating, Moving Solids Bed589

590Moving solids bed subclasses primarily are distinguished by the method or591technology for moving the solids bed.592

593• Paddle594• Rotary (Tumble)595• Agitation596

597g. Indirect Conduction Heating, Static Solids Beds598

599No indirect heating, static solids bed shelf dryer subclasses have been 600identified.601

602h. Indirect Conduction, Lyophilization603

604No lyophilizer subclasses have been identified.605

606i. Gas Stripping607

608Although gas stripping dryers may differ from one another in geometry, shape of609agitator, and how fluidizing gas is moved through the bed, no gas stripping dryer610subclasses have been identified.611

612j. Indirect Radiant Heating, Moving Solids Bed (Microwave Dryer) 613

614Although microwave dryers may differ from one another in vessel 615geometry and the way microwaves are directed into the solids, no616indirect radiant heating, moving solids bed dryer subclasses have been617identified.618

619Note: If a single piece of equipment is capable of performing multiple discrete unit operations620(mixing, granulating, drying), the unit was evaluated solely for its ability to dry. The drying621equipment was sorted into similar classes of equipment, based upon the method of heat transfer622and the dynamics of the solids bed.623

624E. Unit Dosing625



630




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Unit Dosing: The division of a powder blend into uniform single portions for631delivery to patients.632

633b. Operating Principles 634

635i. Tabletting636

637The division of a powder blend in which compression force is 638applied to form a single unit dose.639

640ii. Encapsulating641

642The division of material into a hard gelatin capsule. Encapsulators 643should all have the following operating principles in common: 644rectification (orientation of the hard gelatin capsules), separation of 645capsule caps from bodies, dosing of fill material/formulation, 646rejoining of caps and bodies, and ejection of filled capsules.647

648iii. Powder Filling649

650The division of a powder blend into a container closure system. 651


a. Tablet Press654655

Tablet press subclasses primarily are distinguished from one another by the 656method that the powder blend is delivered to the die cavity. Tablet presses can657deliver powders without mechanical assistance (gravity), with mechanical658assistance (power assisted), by rotational forces (centrifugal), and in two different659locations where a tablet core is formed and subsequently an outer layer of coating660material is applied (compression coating).661

662• Gravity663• Power Assisted664• Centrifugal665• Compression Coating666

667Tablet press subclasses are also distinguished from one another for some special 668types of tablets where more than one hopper and precise powder feeding 669mechanism might be necessary.670

671• Multi-tablet press for micro/mini tablet 672• Multi-layer tablet press (bi-layer, tri-layer)673

674b. Encapsulator675

676




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Encapsulator subclasses primarily are distinguished from one another by the677method that is used for introducing material into the capsule. Encapsulators678can deliver materials with a rotating auger, vacuum, vibration of perforated679plate, tamping into a bored disk (dosing disk), or cylindrical tubes fitted with680pistons (dosator).681

682• Auger683• Vacuum684• Vibratory685• Dosing Disk686• Dosator687

688c. Powder Filler689

690Subclasses of powder fillers primarily are distinguished by the method used to691deliver the predetermined amount for container fill.692

693• Vacuum694• Auger695

696F. Soft Gelatin Capsule697



702i. Gel Mass Preparation: The manufacture of a homogeneous,703

degassed liquid mass (solution) of gelatin, plasticizer, water, and704other additives, either in solution or suspension, such as colorants,705pigments, flavors, preservatives, etc., that comprise a unique 706functional gel shell formation. The operation may be performed in707discreet steps or by continuous processing. Minor components can708be added after the liquid gel mass is made.709

710ii. Fill Mixing: The mixing of either liquids or solids with other liquids 711

to form a solution; blending of limited solubility solid(s) with a 712liquid carrier and suspending agents used to stabilize the blend to 713form a suspension; or the uniform combination of dry inert and drug714active substances to form a dry powder fill suitable for 715encapsulation. The reader should refer to the other sections of this 716document for dry fill manufacture.717

718iii. Encapsulation: The continuous casting of gel ribbons, with liquid 719

fill material being injected between the gel ribbons using a positive 720displacement pump or, for dry materials being gravity or force fed 721with capsule formation using a rotary die.722

723




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iv. Washing: The continuous removal of a lubricant material from the 724outside of the formed capsule. The washing operation is unique to 725each manufacturer’s operation and generally uses in-house 726fabricated equipment. This equipment will not be discussed in this 727guidance document.728

729v. Drying: The removal of the majority of water from the capsule’s 730

gel shell by tumbling and subsequent tray drying using conditioned 731air, which enhances the size, shape, and shell physical properties of 732the final product. The drying operation is unique to each 733manufacturer’s operation and generally uses in-house fabricated734equipment. This equipment will not be discussed in this guidance 735document.736

737vi. Inspection/Sorting: The process wherein undesirable capsules are 738

removed, including misshapen, leaking, and unfilled capsules as739well as agglomerates of capsules.740

741vii. Printing: The marking of a capsule surface for the purpose of 742

product identification, using a suitable printing media or method.743744

b. Operating Principles 745746

i. Mixing747748

The combination of solid and liquid components, including 749suspending aid(s) at either ambient or elevated temperatures to 750form a solution, suspension, or dry powder blend for the 751manufacture of gel mass or fill material. Mixing also includes752the incorporation of minor components into the liquid gel mass.753

754ii. Deaggregation755

756The removal of aggregates using a suitable homogenizer/mill to 757provide a pumpable fill material. The procedure has minimal758effect on the particle size distribution of the initial solid759component(s), and is viewed as a processing aid.9760

761iii. Deaeration762

763The removal of entrapped air from either the gel mass or fill 764material, solution or suspension. This process can take place in 765either the mixing vessel, through the application of vacuum, or766a separate off-line step.767

768

9 Carstensen, J. T., Theory of Pharmaceutical Systems, Volume 11 Heterogeneous Systems, Academic Press, New York,NY, 1973, p 51.




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iv. Holding769770

The storage of liquid gel mass or fill material in a vessel, with771a mixer or without, prior to encapsulation, which also may be 772equipped with a jacket for either heating or cooling.773

774v. Encapsulation775

776The formation of capsules using a rotary die machine.10777

778vi. Inspection/Sorting779

780The physical removal of misshapen, leaking, or781agglomerated capsules, using either a manual or automatic782operation.783

784vii. Printing785

786The user of this document is asked to refer to the coating/printing 787section, in which the use of various pieces of equipment are defined 788and categorized.789


792a. Mixers and Mixing Vessels793

794Mixer and mixing vessel subclasses primarily are distinguished by the mixing795energy, mixer type, and whether a jacketed vessel with vacuum capabilities is796used in conjunction with a specific mixer.797

798• Low Energy Mixer799• High Energy Mixer800• Planetary801• Jacketed Vessel With and Without Vacuum802

803b. Deaggregators804

805Deaggregator subclasses primarily are distinguished by the type of 806mechanical action imparted to the material.807

808• Rotor/Stator809

10 Lachman, L., H. A. Lieberman, and J. L. Kanig (Eds.), The Theory and Practice of Industrial Pharmacy,Chapter 3, p. 359 (Stanley, J. P.), Philadelphia Lea & Febiger, 1971; Tyle, P. (Ed.), Specialized DrugDelivery Systems, Manufacturing and Production Technology, Chapter 10, p. 409 (Wilkinson, P.K. and F.S.Hom), New York; M. Dekker, 1990; Porter, S., Remington’s Pharmaceutical Sciences, Edition 18, Chapter89, pp. 1662 - 1665, Easton, Penn.: Mack Publishing Co.




19

• Roller810• Cutting Mills811• Stone Mills812• Tumbling Mills813

814c. Deaerators815

816Deaerator subclasses primarily are distinguished by the air removal path, either817through the bulk or through a thin film, and whether it is a batch or in-line818process.819

820• Vacuum Vessel821• Off Line/In Line822

823d. Holding Vessels824

825Although holding vessels may differ from one another, based upon whether they826are jacketed, with and without integrated mixing capabilities, no holding vessel827subclasses have been identified.828

829• Jacketed vessel with and without mixing system830

831e. Encapsulators832

833Encapsulator subclasses primarily are distinguished by the method used to inject834the fill material.835

836• Positive Displacement Pump837• Gravity or Force Fed838

839f. Inspection/Sorting840

841Inspection/sorting equipment subclasses primarily are distinguished by the 842method used to present the capsule for viewing and mechanical method of 843separation.844

845• Belt846• Vibratory847• Roller848• Rotary Table849• Electromechanical850

851G. Coating/Printing/Drilling852


855




20

a. Unit Operation856857

i. Coating: The uniform deposition of a layer of material on858or around a solid dosage form, or component thereof, to:859

860a. Protect the drug from its surrounding environment861

(air, moisture, and light), with a view to improving862stability.863

b. Mask unpleasant taste, odor, or color of the drug.864c. Increase the ease of ingesting the product for the patient.865d. Impart a characteristic appearance to the tablets, which 866

facilitates product identification and aids patient867compliance.868

e. Provide physical protection to facilitate handling. This869includes minimizing dust generation in subsequent unit 870operations.871

f. Reduce the risk of interaction between incompatible872components. This would be achieved by coating one or 873more of the offending ingredients.874

g. Modify the release of drug from the dosage form. This875includes delaying, extending, and sustaining drug substance 876release.877

h. Modify the dosage form by depositing the API or drug 878substance on or around a core tablet, which could be a 879placebo core tablet or a tablet containing another drug or a 880fractional quantity of the same drug.881

882The coating material deposition typically is accomplished883through one of six major techniques:884

885a. Sugar Coating - Deposition of coating material onto886

the substrate from aqueous solution/suspension of887coatings, based predominately upon sucrose as a raw888material.889

b. Film Coating - The deposition of polymeric film onto890the solid dosage form.891

c. Core Enrobing - The gelatin coating of gravity or force892fed pre- formed tablets or caplets.893

d. Microencapsulation - The deposition of a coating material 894onto a particle, pellet, granule, or bead core. The895substrate in this application ranges in size from submicron896to several millimeters. It is this size range that897differentiates it from the standard coating described in 1898and 2 above.899

e. Compression Coating (also addressed in the Unit Dosing900section) - A coating process where a dry coatings blend is 901applied on a previously compressed core tablet using a 902




21

tablet compression machine.11 Therefore, this process is 903also known as a dry coating process that does not involve 904any water or any other solvent in the coating process.905

f. Active/API coating - Deposition of active pharmaceutical 906ingredient (API or drug substance) on or around a core 907tablet utilizing any of the above five coating techniques.908

909ii. Printing: The marking of a capsule or tablet surface for the910

purpose of product identification. Printing may be accomplished911by either the application of a contrasting colored polymer (ink)912onto the surface of a capsule or tablet, or by the use of laser913etching.914

915The method of application, provided the ink formulation is not 916altered, is of no consequence to the physical-chemical properties of 917the product.918

919iii. Drilling: The drilling or ablating of a hole or holes through the 920

polymeric film coating shell on the surfaces of a solid oral dosage 921form using a laser. The polymeric film shell is not soluble in922vivo. The hole or holes allow for the modified release of the drug923from the core of the dosage form.924

925b. Operating Principles 926

927i. Pan Coating928

The uniform deposition of coating material onto the surface of a929solid dosage form, or component thereof, while being translated via 930a rotating vessel.931

932ii. Gas Suspension933

934The application of a coating material onto a solid dosage form, or 935component thereof, while being entrained in a process gas stream.936

937Alternatively, this may be accomplished simultaneously by938spraying the coating material and substrate into a process gas939stream.940

941iii. Vacuum Film Coating942

943

11 W.C. Gunsel & R.G. Dusel. Compression-coated and layer tablets. In H.A.Lieberman, L. Lachman & B. Schwartz (Eds), Pharmaceutical Dosage Forms: Tablets Vol 1, 1989, pp. 247-249. Mercel Dekker, Inc.




22

This technique uses a jacketed pan equipped with a baffle system. 944Tablets are placed into the sealed pan, an inert gas (i.e., nitrogen)945is used to displace the air and then a vacuum is drawn.946

947iv. Dip Coating948

949Coating is applied to the substrate by dipping it into the950coating material. Drying is accomplished using pan coating951equipment.952

953v. Electrostatic Coating954

955A strong electrostatic charge is applied to the surface of the956substrate. The coating material containing oppositely charged ionic 957species is sprayed onto the substrate.958

959vi. Compression Coating960

961Refer to the Unit Dosing section of this document. 962

vii. Ink-Based Printing963

The application of contrasting colored polymer (ink) onto964the surface of a tablet or capsule.965

966viii. Laser Etching967

968The application of identifying markings onto the surface of a 969tablet or capsule using laser-based technology.970

971ix. Drilling972

973A drilling system typically is a custom built unit consisting of a974material handling system to orient and hold the solid dosage form,975a laser (or lasers), and optics (lenses, mirrors, deflectors, etc.) to 976ablate the hole or holes, and controls. The drilling unit may include 977debris extraction and inspection systems as well. The sorting, 978orienting, and holding equipment commonly is provided by dosage 979form printing equipment manufacturers, and is considered ancillary 980in this use.981


984a. Pan Coating985

986Pan coating subclasses primarily are distinguished by the pan configuration, the987pan perforations, and/or the perforated device used to introduce process air for988




23

drying purposes. Perforated coating systems include both batch and continuous989coating processes.990

991• Non-perforated (conventional) Coating System992• Perforated Coating System993

994b. Gas Suspension995

996Gas suspension subclasses primarily are distinguished by the method997by which the coating is applied to the substrate.998

999• Fluidized Bed with bottom spray mechanism1000• Fluidized Bed with tangential spray mechanism1001• Fluidized Bed with top spray mechanism1002• Fluidized Bed with Wurster column 1003• Spray Congealing/Drying1004

1005c. Vacuum Film Coating1006

1007Although there may be differences in the jacketed pan, baffle system, or 1008vacuum source, no vacuum film coating subclasses have been identified.1009

1010d. Dip Coating1011

1012Because of the custom design associated with this class of coating, no dip 1013coating subclasses or examples have been identified.1014

1015e. Electrostatic Coating1016

1017Because of the custom design associated with this class of coating, no1018electrostatic coating subclasses or examples have been identified.1019

1020f. Compression Coating1021

1022Refer to the Unit Dosing section of this document.1023

1024g. Ink-Based Printing1025

1026Ink-based printing subclasses primarily are distinguished by the method by which1027the marking is applied to a capsule or tablet surface.1028

1029• Offset1030• Ink Jet1031

1032h. Laser Etching (Printing)1033

1034




24

Although laser etching systems may differ from one another, no laser 1035etching subclasses have been identified.1036

1037i. Drilling1038

1039The method of producing the laser pulse that ablates the hole(s) is of no 1040consequence to the physical-chemical properties of the product. Therefore, no1041dosage form drilling equipment subclasses have been identified.1042

1043V. SUPAC-SS INFORMATION1044

1045A. Particle Size Reduction/Separation1046

1047The same definition and classification applies as described in section IV. A. for IR/MR 1048products.1049

1050B. Mixing1051



1056Mixing: The reorientation of particles relative to one another to achieve 1057uniformity or randomness. This process can include wetting of solids by a liquid 1058phase, dispersion of discrete particles, or deagglomeration into a continuous1059phase. Heating and cooling via indirect conduction may be used in this operation1060to facilitate phase mixing or stabilization.1061


1064i. Convection Mixing, Low Shear: Mixing process with a repeated1065

pattern of cycling material from top to bottom, in which dispersion1066occurs under low power per unit mass through rotating low shear1067forces.1068

1069ii. Convection Mixing, High Shear: Mixing process with a repeated1070

pattern of cycling material from top to bottom, in which dispersion1071occurs under high power per unit mass through rotating high shear1072forces.1073

1074iii. Roller Mixing (Milling): Mixing process by high mechanical1075

shearing action where compression stress is achieved by passing1076material between a series of rotating rolls. This is commonly1077referred to as compression or roller milling.1078

1079




25

iv. Static Mixing: Mixing process in which material passes through a 1080tube with stationary baffles. The mixer is generally used in1081conjunction with an in-line pump.1082


1085a. Convection Mixers, Low Shear1086

1087This group normally operates under low shear conditions and is broken down by 1088impeller design and movement. Design can also include a jacketed vessel to 1089facilitate heat transfer.1090

1091• Anchor or sweepgate1092• Impeller1093• Planetary1094

1095b. Convection Mixers, High Shear1096

1097This group normally operates only under high shear conditions. Subclasses are 1098differentiated by how the high shear is introduced into the material, such as by a 1099dispersator with serrated blades or homogenizer with rotor stator.1100

1101• Dispersator1102• Rotor stator1103

1104c. Roller Mixers (Mills)1105

1106No roller mixer subclasses have been identified.1107

1108d. Static Mixers1109

1110No static mixer subclasses have been identified.1111

11121113

Note: If a single piece of equipment is capable of performing multiple discrete unit operations,1114it has been evaluated solely for its ability to mix materials.1115

1116C. Emulsification1117



1122Emulsification: The application of physical energy to a liquid system consisting of 1123at least two immiscible phases, causing one phase to be dispersed into the other.1124


1127




26

i. Low Shear Emulsification: Use of low shear energy using1128mechanical mixing with an impeller to achieve a dispersion of the1129mixture. The effectiveness of this operation is especially dependent1130on proper formulation.1131

1132ii. High Shear Emulsification: Use of high shear energy to1133

achieve a dispersion of the immiscible phases. High shear can1134be achieved by the following means:1135

1136a. Stirring the mixture with a high speed chopper or1137

saw-tooth dispersator.11381139

b. Passing the mixture through the gap between a high-1140speed rotor and a stationary stator.1141

1142c. Passing the mixture through a small orifice at high pressure1143

(valve- type homogenizer) or through a small orifice at high1144pressure followed by impact against a hard surface or1145opposing stream (valve-impactor type homogenizer),1146causing sudden changes of pressure.1147


1150a. Low Shear Emulsifiers1151

1152Although low shear emulsification equipment (mechanical stirrers or impellers)1153can differ in the type of fluid flow imparted to the mixture (axial-flow propeller or 1154radial-flow turbines), no subclasses have been defined.1155

1156b. High Shear Emulsifiers1157

1158Subclasses of high shear emulsification equipment differ in the method used1159to generate high shear.1160

1161• Dispersator1162• Rotor stator1163• Valve or pressure homogenizer1164

1165Note: If a single piece of equipment is capable of performing multiple discrete unit1166operations, the unit has been evaluated solely for its ability to emulsify materials.1167

1168D. Deaeration1169



1174




27

Deaeration: The elimination of trapped gases to provide more accurate 1175volumetric measurements and remove potentially reactive gases.1176


1179The use of vacuum or negative pressure, alone or in combination with mechanical 1180intervention or assistance.1181


1184a. Deaerators1185

1186Deaerator subclasses differ primarily in their air removal paths, either through the 1187bulk material or through a thin film, and in whether they use a batch or in-line 1188process.1189

1190• Off-Line or in-line1191• Vacuum vessel1192

1193Note: If a single piece of equipment is capable of performing multiple discrete unit operations,1194it has been evaluated solely for its ability to deaerate materials.1195

1196E. Transfer1197

11981. Definition1199


1202Transfer: The controlled movement or transfer of materials from one location to 1203another.1204


1207i. Passive: The movement of materials across a non-mechanically-1208

induced pressure gradient, usually through conduit or pipe.12091210

ii. Active: The movement of materials across a mechanically-1211induced pressure gradient, usually through conduit or pipe.1212


1215a. Low Shear1216

1217Active or passive material transfer, with a low degree of induced shear1218

1219• Diaphragm1220• Gravity1221• Peristaltic1222• Piston1223• Pneumatic1224• Rotating lobe1225• Screw or helical screw1226

1227b. High Shear1228

1229




28

Active or mechanical material transfer with a high degree of induced shear12301231

• Centrifugal or turbine1232• Piston1233• Rotating gear1234

1235Note: This section is intended to deal with the transfer of shear sensitive materials, including 1236product or partially manufactured product. A single piece of equipment can be placed in either a1237low or high shear class, depending on its operating parameters. If a single piece of equipment is 1238capable of performing multiple discrete unit operations, the unit has been evaluated solely for its 1239ability to transfer materials.1240

1241F. Packaging1242



1247i. Holding: The process of storing product after completion of 1248

manufacturing process and prior to filling final primary packs.12491250

ii. Transfer: The process of relocating bulk finished product from1251holding to filling equipment using pipe, hose, pumps and/or other 1252associated components.1253

1254iii. Filling: The delivery of target weight or volume of bulk finished 1255

product to primary pack containers12561257

iv. Sealing: A device or process for closing and/or sealing primary 1258pack containers following the filling process.1259


1262i. Holding: The storage of liquid, semi-solids, or product1263

materials in a vessel that may or may not have temperature1264control and/or agitation.1265

1266ii. Transfer: The controlled movement or transfer of materials1267

from one location to another.12681269

iii. Filling: Filling operating principles involve several associated 1270subprinciples. The primary package can be precleaned to remove 1271particulates or other materials by the use of ionized air, vacuum,1272or inversion. A holding vessel equipped with an auger, gravity, or1273pressure material feeding system should be used. The vessel may1274or may not be able to control temperature and/or agitation. Actual1275filling of the dosage form into primary containers can involve a 1276metering system based on an auger, gear, orifice, peristaltic, or1277piston pump. A head-space blanketing system can also be used.1278




29

1279iv. Sealing: Primary packages can be sealed using a variety of1280

methods, including conducted heat and electromagnetic1281(induction or microwave) or mechanical manipulation (crimping1282or torquing).1283


1286a. Holders1287

1288Although holding vessels can differ in their geometry and ability to control 1289temperature or agitation, their primary differences are based on how materials1290are fed.1291

1292• Auger1293• Gravity1294• Pneumatic (nitrogen, air, etc.)1295

1296b. Fillers1297

1298The primary differences in filling equipment are based on how materials1299are metered.1300

1301• Auger1302• Gear pump1303• Orifice1304• Peristaltic pump1305• Piston1306

1307c. Sealers1308

1309The differences in primary container sealing are based on how energy is1310transferred or applied.1311

1312• Heat1313• Induction1314• Microwave1315• Mechanical or crimping1316• Torque1317

13181319

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