The AAPS Journal, Vol. 16, No. 4, July 2014 ( # 2014)
`DOI: 10.1208/s12248-014-9598-3
`
`Review Article
`
`Understanding Pharmaceutical Quality by Design
`
`Lawrence X. Yu,1,6 Gregory Amidon,2 Mansoor A. Khan,1 Stephen W. Hoag,3 James Polli,3
`G. K. Raju,4,5 and Janet Woodcock1
`
`Received 17 November 2013; accepted 24 March 2014; published online 23 May 2014
`
`Abstract. This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes
`its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies
`the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including
`identification of critical material attributes (CMAs); (3) process design and understanding including
`identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy
`that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for
`each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and
`studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data
`analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the
`implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations
`are necessary. This understanding will facilitate better communication between those involved in risk-based
`drug development and drug application review.
`
`KEY WORDS: control strategy; critical quality attributes; pharmaceutical quality by design; process
`understanding; product understanding.
`
`INTRODUCTION
`
`Quality by design (QbD) is a concept first developed by the
`quality pioneer Dr. Joseph M. Juran (1). Dr. Juran believed that
`quality should be designed into a product, and that most quality
`crises and problems relate to the way in which a product was
`designed in the first place. Woodcock (2) defined a high-quality
`drug product as a product free of contamination and reliably
`delivering the therapeutic benefit promised in the label to the
`consumer. The US Food and Drug Administration (FDA)
`encourages risk-based approaches and the adoption of QbD
`principles in drug product development, manufacturing, and
`regulation. FDA’s emphasis on QbD began with the recognition
`that increased testing does not necessarily improve product
`quality. Quality must be built into the product.
`Over the years, pharmaceutical QbD has evolved with the
`issuance of ICH Q8 (R2) (Pharmaceutical Development), ICH
`Q9 (Quality Risk Management), and ICH Q10 (Pharmaceutical
`Quality System) (3–5). In addition, the ICH Q1WG on Q8, Q9,
`and Q10 Questions and Answers; the ICH Q8/Q9/Q10 Points to
`
`1 Center for Drug Evaluation and Research, Food and Drug
`Administration, Silver Spring, Maryland 20993, USA.
`2 University of Michigan, Ann Arbor, Michigan 48109, USA.
`3 University of Maryland, Baltimore, Maryland 21201, USA.
`4 Massachusetts Institute of Technology, Cambridge, Massachusetts
`02139, USA.
`5 Light Pharm Inc., Cambridge, Massachusetts 02142, USA.
`6 To whom correspondence should be addressed. (e-mail:
`lawrence.yu@fda.hhs.gov)
`
`Consider document; and ICH Q11 (Development and Manu-
`facture of Drug Substance) have been issued, as have the
`conclusions of FDA-EMA’s parallel assessment of Quality-By-
`Design elements of marketing applications (6–9). These docu-
`ments provide high level directions with respect to the scope and
`definition of QbD as it applies to the pharmaceutical industry.
`Nonetheless, many implementation details are not
`discussed in these guidances or documents. There is confusion
`among industry scientists, academicians, and regulators despite
`recent publications (10–13). This paper is intended to describe
`the objectives of pharmaceutical QbD, detail its concept and
`elements, and explain implementation tools and studies.
`
`PHARMACEUTICAL QUALITY BY DESIGN
`OBJECTIVES
`
`Pharmaceutical QbD is a systematic approach to devel-
`opment that begins with predefined objectives and empha-
`sizes product and process understanding and control based on
`sound science and quality risk management (3). The goals of
`pharmaceutical QbD may include the following:
`
`1. To achieve meaningful product quality specifications
`that are based on clinical performance
`2. To increase process capability and reduce product
`variability and defects by enhancing product and
`process design, understanding, and control
`3. To increase product development and manufacturing
`efficiencies
`4. To enhance root cause analysis and postapproval
`change management
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`Under QbD, these goals can often be achieved by
`linking product quality to the desired clinical performance
`and then designing a robust formulation and manufactur-
`ing process to consistently deliver the desired product
`quality.
`Since the initiation of pharmaceutical QbD, the FDA
`has made significant progress
`in achieving the first
`objective: performance-based quality specifications. Some
`examples of FDA policies include tablet scoring and bead
`sizes in capsules labeled for sprinkle (14,15). The recent
`FDA discussions on the assayed potency limits for narrow
`therapeutic index drugs and physical attributes of generic
`drug products
`reflect
`this
`trend (16). Nonetheless,
`it
`should be recognized that ICH documents (3–9) did not
`explicitly acknowledge clinical performance-based specifi-
`cations as a QbD goal, although this was recognized in a
`recent scientific paper (10).
`The second objective of pharmaceutical QbD is to
`increase process capability and reduce product variability
`that often leads to product defects, rejections, and recalls.
`Achieving this objective requires robustly designed prod-
`uct and process. In addition, an improved product and
`process understanding can facilitate the identification and
`control of
`factors influencing the drug product quality.
`After
`regulatory approval, effort
`should continue to
`improve the process to reduce product variability, defects,
`rejections, and recalls.
`QbD uses a systematic approach to product design and
`development. As such,
`it enhances development capability,
`speed, and formulation design. Furthermore,
`it transfers
`resources
`from a downstream corrective mode to an
`upstream proactive mode. It enhances the manufacturer’s
`ability to identify the root causes of manufacturing
`failures. Hence,
`increasing product development and
`manufacturing efficiencies is the third objective of phar-
`maceutical QbD.
`The final objective of QbD is to enhance root cause
`analysis and postapproval change management. Without good
`product and process understanding, the ability to efficiently
`scale-up and conduct root cause analysis is limited and
`requires the generation of additional data sets on the
`proposed larger scale. FDA’s change guidances (17,18)
`provide a framework for postapproval changes. Recently,
`the FDA issued a guidance intended to reduce the regulatory
`filing requirements
`for
`specific low-risk chemistry,
`manufacturing, and control (CMC) postapproval manufactur-
`ing changes (19).
`
`ELEMENTS OF PHARMACEUTICAL QUALITY
`BY DESIGN
`
`In a pharmaceutical QbD approach to product develop-
`ment, an applicant identifies characteristics that are critical to
`quality from the patient’s perspective, translates them into the
`drug product critical quality attributes (CQAs), and estab-
`lishes the relationship between formulation/manufacturing
`variables and CQAs to consistently deliver a drug product
`with such CQAs to the patient. QbD consists of the following
`elements:
`
`Yu et al.
`
`1. A quality target product profile (QTPP) that identifies
`the critical quality attributes (CQAs) of the drug
`product
`2. Product design and understanding including the
`identification of critical material attributes (CMAs)
`3. Process design and understanding including the iden-
`tification of critical process parameters (CPPs) and a
`thorough understanding of scale-up principles, linking
`CMAs and CPPs to CQAs
`4. A control strategy that includes specifications for the
`drug substance(s), excipient(s), and drug product as
`well as controls for each step of the manufacturing
`process
`5. Process capability and continual improvement
`
`Quality Target Product Profile that Identifies the Critical
`Quality Attributes of the Drug Product
`
`QTPP is a prospective summary of the quality charac-
`teristics of a drug product that ideally will be achieved to
`ensure the desired quality, taking into account safety and
`efficacy of the drug product. QTPP forms the basis of design
`for the development of
`the product. Considerations for
`inclusion in the QTPP could include the following (3):
`
`& Intended use in a clinical setting, route of adminis-
`tration, dosage form, and delivery system(s)
`& Dosage strength(s)
`& Container closure system
`& Therapeutic moiety release or delivery and attributes
`affecting pharmacokinetic characteristics (e.g., disso-
`lution and aerodynamic performance) appropriate to
`the drug product dosage form being developed
`& Drug product quality criteria (e.g., sterility, purity,
`stability, and drug release) appropriate for the
`intended marketed product
`
`Identification of the CQAs of the drug product is the
`next step in drug product development. A CQA is a
`physical, chemical, biological, or microbiological property
`or characteristic of an output material
`including finished
`drug product that should be within an appropriate limit,
`range, or distribution to ensure the desired product
`quality (3). The quality attributes of a drug product may
`include identity, assay, content uniformity, degradation
`products, residual solvents, drug release or dissolution,
`moisture content, microbial limits, and physical attributes
`such as color, shape, size, odor, score configuration, and
`friability. These attributes can be critical or not critical.
`Criticality of an attribute is primarily based upon the
`severity of harm to the patient should the product fall
`outside the acceptable range for that attribute. Probability
`of occurrence, detectability, or controllability does not
`impact criticality of an attribute.
`It seems obvious that a new product should be ade-
`quately defined before any development work commences.
`However, over the years, the value of predefining the target
`characteristics of the drug product is often underestimated.
`Consequently, the lack of a well-defined QTPP has resulted in
`wasted time and valuable resources. A recent paper by Raw
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`et al. (12) illustrates the significance of defining the correct
`QTPP before conducting any development. Also, QbD exam-
`ples exemplify the identification and use of QTPPs (20–22).
`
`Product Design and Understanding
`
`Over the years, QbD’s focus has been on the process
`design, understanding, and control, as discussed in the ICH
`Q8 (R2) guidance (3). It should be emphasized that product
`design, understanding, and control are equally important.
`Product design determines whether the product is able to
`meet patients’ needs, which is confirmed with clinical studies.
`Product design also determines whether the product is able to
`maintain its performance through its shelf life, which is
`confirmed with stability studies. This type of product under-
`standing could have prevented some historical stability
`failures.
`The key objective of product design and understanding is
`to develop a robust product that can deliver the desired
`QTPP over the product shelf life. Product design is open-
`ended and may allow for many design pathways. Key
`elements of product design and understanding include the
`following:
`
`& Physical, chemical, and biological characterization of
`the drug substance(s)
`& Identification and selection of excipient type and
`grade, and knowledge of intrinsic excipient variability
`& Interactions of drug and excipients
`& Optimization of formulation and identification of
`CMAs of both excipients and drug substance
`
`To design and develop a robust drug product that has the
`intended CQAs, a product development scientist must give
`serious consideration to the physical, chemical, and biological
`properties of the drug substance. Physical properties include
`physical description (particle size distribution and particle
`morphology), polymorphism and form transformation, aqueous
`solubility as a function of pH,
`intrinsic dissolution rate,
`hygroscopicity, and melting point(s). Pharmaceutical solid
`polymorphism, for example, has received much attention
`recently since it can impact solubility, dissolution, stability, and
`manufacturability. Chemical properties include pKa, chemical
`stability in solid state and in solution, as well as photolytic and
`oxidative stability. Biological properties include partition coef-
`ficient, membrane permeability, and bioavailability.
`Pharmaceutical excipients are components of a drug
`product other than the active pharmaceutical
`ingredient.
`Excipients can (1) aid in the processing of the dosage
`form during its manufacture; (2) protect,
`support, or
`enhance stability, bioavailability, or patient acceptability;
`(3) assist
`in product
`identification; or (4) enhance any
`other attribute of
`the overall safety, effectiveness, or
`delivery of
`the drug during storage or use (23). They
`are classified by the functions they perform in a pharma-
`ceutical dosage form. Among 42 functional excipient
`categories listed in USP/NF (24), commonly used excipi-
`ents include binders, disintegrants, fillers (diluents), lubri-
`cants, glidants (flow enhancers), compression aids, colors,
`sweeteners, preservatives,
`suspending/dispersing agents,
`pH modifiers/buffers, tonicity agents, film formers/coatings,
`flavors, and printing inks. The FDA’s inactive ingredients
`
`database (25) lists the safety limits of excipients based on
`prior use in FDA-approved drug products.
`It is well recognized that excipients can be a major
`source of variability. Despite the fact that excipients can alter
`the stability, manufacturability, and bioavailability of drug
`products, the general principles of excipient selection are not
`well-defined, and excipients are often selected ad hoc without
`systematic drug-excipient compatibility testing. To avoid
`costly material wastage and time delays, ICH Q8 (R2)
`recommends drug-excipient compatibility studies to facilitate
`the early prediction of compatibility (3). Systematic drug-
`excipient compatibility studies offer several advantages as
`follows: minimizing unexpected stability failures which usual-
`ly lead to increased development time and cost, maximizing
`the stability of a formulation and hence the shelf life of the
`drug product, and enhancing the understanding of drug-
`excipient interactions that can help with root cause analysis
`should stability problems occur.
`Formulation optimization studies are essential in developing a
`robust formulation that is not on the edge of failure. Without
`optimization studies, a formulation is more likely to be high risk
`because it is unknown whether any changes in the formulation itself
`or in the raw material properties would significantly impact the
`quality and performance of the drug product, as shown in recent
`examples (26,27). Formulation optimization studies provide impor-
`tant information on the following:
`
`& Robustness of the formulation including establishing
`functional relationships between CQAs and CMAs
`& Identification of CMAs of drug substance, excipients,
`and in-process materials
`& Development of control strategies for drug substance
`and excipients
`
`In a QbD approach, it is not the number of optimization
`studies conducted but rather the relevance of the studies and
`the utility of the knowledge gained for designing a quality
`drug product that is paramount. As such, the QbD does not
`equal design of experiments (DoE), but the latter could be an
`important component of QbD.
`Drug substance, excipients, and in-process materials may
`have many CMAs. A CMA is a physical, chemical, biological,
`or microbiological property or characteristic of an input
`material that should be within an appropriate limit, range,
`or distribution to ensure the desired quality of that drug
`substance, excipient, or in-process material. For the purpose
`of this paper, CMAs are considered different from CQAs in
`that CQAs are for output materials including product
`intermediates and finished drug product while CMAs are for
`input materials including drug substance and excipients. The
`CQA of an intermediate may become a CMA of that same
`intermediate for a downstream manufacturing step.
`Since there are many attributes of the drug substance
`and excipients that could potentially impact the CQAs of the
`intermediates and finished drug product, it is unrealistic that a
`formulation scientist investigate all the identified material
`attributes during the formulation optimization studies. There-
`fore, a risk assessment would be valuable in prioritizing which
`material attributes warrant further study. The assessment
`should leverage common scientific knowledge and the
`formulator’s expertise. A material attribute is critical when a
`realistic change in that material attribute can have a
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`Table I. Typical Input Material Attributes, Process Parameters, and Quality Attributes of Pharmaceutical Unit Operations
`
`Pharmaceutical unit operation
`
`Input material attributes
`
`(cid:129) Particle size
`(cid:129) Particle size distribution
`(cid:129) Fines/oversize
`(cid:129) Particle shape
`(cid:129) Bulk/tapped/true density
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Moisture content
`
`(cid:129) Particle/granule size
`(cid:129) Particle/granule size
`distribution
`(cid:129) Fines
`(cid:129) Particle/granule shape
`(cid:129) Bulk/tapped/true density
`(cid:129) Adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`(cid:129) Solid form/polymorph
`(cid:129) Moisture content
`(cid:129) Granule porosity/density
`
`(cid:129) Particle size distribution
`(cid:129) Fines/Oversize
`(cid:129) Particle shape
`(cid:129) Bulk/tapped/true density
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`(cid:129) Solid form/polymorph
`(cid:129) Moisture content
`
`Process parameters
`Blending/mixing
`(cid:129) Type and geometry of mixer
`(cid:129) Mixer load level
`(cid:129) Order of addition
`(cid:129) Number of revolutions (time and speed)
`(cid:129) Agitating bar (on/off pattern)
`(cid:129) Discharge method
`(cid:129) Holding time
`(cid:129) Environment temperature and RH
`
`Size reduction/comminution
`
`Ribbon milling
`(cid:129) Ribbon dimensions
`(cid:129) Ribbon density
`(cid:129) Ribbon porosity/solid fraction
`
`Impact/cutting/screening mills
`(cid:129) Mill type
`(cid:129) Speed
`(cid:129) Blade configuration, type, orientation
`(cid:129) Screen size and type
`(cid:129) Feeding rate
`
`Fluid energy mill
`(cid:129) Number of grinding nozzles
`(cid:129) Feed rate
`(cid:129) Nozzle pressure
`(cid:129) Classifier
`
`Granule/ribbon milling
`(cid:129) Mill type
`(cid:129) Speed
`(cid:129) Blade configuration, type, orientation
`(cid:129) Screen size and type
`(cid:129) Feeding rate
`
`location, power
`
`Wet granulation
`High/low shear granulation
`(cid:129) Type of granulator (High/low shear, top/bottom drive)
`(cid:129) Fill level
`(cid:129) Pregranulation mix time
`(cid:129) Granulating liquid or solvent quantity
`(cid:129) Impeller speed, tip speed, configuration,
`consumption/torque
`(cid:129) Chopper speed, configuration, location, power consumption
`(cid:129) Spray nozzle type and location
`(cid:129) Method of binder excipient addition (dry/wet)
`(cid:129) Method of granulating liquid addition (spray or pump)
`(cid:129) granulating liquid temperature
`(cid:129) granulating liquid addition rate and time
`(cid:129) Wet massing time (post-granulation mix time)
`(cid:129) Bowl temperature(jacket temperature)
`(cid:129) Product temperature
`(cid:129) Post mixing time
`(cid:129) Pump Type: Peristaltic, Gear type
`(cid:129) Granulating liquid vessel (e.g., pressurized, heated)
`
`Fluid bed granulation
`(cid:129) Type of fluid bed
`(cid:129) Inlet air distribution plate
`(cid:129) Spray nozzle (tip size, type/quantity/ pattern/configuration/position)
`(cid:129) Filter type and orifice size
`
`Quality attributes
`
`(cid:129) Blend uniformity
`(cid:129) Potency
`(cid:129) Particle size
`(cid:129) Particle size distribution
`(cid:129) Bulk/tapped/true density
`(cid:129) Moisture content
`(cid:129) Flow properties
`(cid:129) Cohesive/adhesive properties
`(cid:129) Powder segregation
`(cid:129) Electrostatic properties
`
`(cid:129) Particle/granule size
`(cid:129) Particle/granule size distribution
`(cid:129) Particle/granule shape
`(cid:129) Particle/granule shape factor
`(e.g., aspect ratio)
`(cid:129) Particle/granule density/Porosity
`(cid:129) Bulk/tapped/true density
`(cid:129) Flow properties
`(cid:129) API polymorphic form
`(cid:129) API crystalline morphology
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/Plasticity
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`
`torque,
`
`(cid:129) Endpoint measurement
`(e.g., power consumption,
`etc.)
`(cid:129) Blend uniformity
`(cid:129) Potency
`(cid:129) Flow
`(cid:129) Moisture content
`(cid:129) Particle size and distribution
`(cid:129) Granule size and distribution
`(cid:129) Granule strength and uniformity
`(cid:129) Bulk/tapped/true density
`(cid:129) API polymorphic form
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Granule brittleness
`(cid:129) Granule elasticity
`(cid:129) Solid form/polymorph
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`Pharmaceutical unit operation
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`Input material attributes
`
`Process parameters
`
`Quality attributes
`
`Table I. (continued)
`
`(cid:129) Fill level
`(cid:129) Bottom screen size and type
`(cid:129) Preheating temperature/time
`(cid:129) Method of binder excipient addition (dry/wet)
`(cid:129) Granulating liquid temperature
`(cid:129) Granulating liquid quantity
`(cid:129) Granulating liquid concentration/viscosity
`(cid:129) Granulating liquid holding time
`(cid:129) Granulating liquid delivery method
`(cid:129) Granulating liquid spray rate
`(cid:129)
`Inlet air, volume, temperature, dew point
`(cid:129) Atomization air pressure
`(cid:129) Product and filter pressure differentials
`(cid:129) Product temperature
`(cid:129) Exhaust air temperature, flow
`(cid:129) Filter shaking interval and duration
`
`Drying
`
`Fluidized bed
`(cid:129)
`Inlet air volume, temperature, dew point
`(cid:129) Product temperature
`(cid:129) Exhaust air temperature, flow
`(cid:129) Filter type and orifice size
`(cid:129) Shaking interval and duration
`(cid:129) Total drying time
`
`Tray
`(cid:129) Type of tray dryer
`(cid:129) Bed thickness/tray depth (depth of product per tray)
`(cid:129) Type of drying tray liner (e.g., paper, plastic,
`synthetic fiber, etc.)
`(cid:129) Quantity carts and trays per chamber
`(cid:129) Quantity of product per tray
`(cid:129) Drying time and temperature
`(cid:129) Air flow
`(cid:129)
`Inlet dew point
`
`Vacuum/microwave
`(cid:129)
`Jacket temperature
`(cid:129) Condenser temperature
`(cid:129)
`Impeller speed
`(cid:129) Bleed air volume
`(cid:129) Vacuum pressure
`(cid:129) Microwave power
`(cid:129) Electric field
`(cid:129) Energy supplied
`(cid:129) Product temperature
`(cid:129) Bowl and lid temperature
`(cid:129) Total drying time
`Roller compaction/chilsonation
`(cid:129) Type of roller compactor
`(cid:129) Auger (feed screw) type/design (horizontal,
`vertical or angular)
`(cid:129) Deaeration (e.g., vacuum)
`(cid:129) Auger (feed screw) speed
`(cid:129) Roll shape (cylindrical or interlocking).
`(cid:129) Roll surface design (smooth, knurled, serrated,
`or pocketed)
`(cid:129) Roll gap width (e.g., flexible or fixed)
`(cid:129) Roll speed
`(cid:129) Roll pressure
`
`(cid:129) Particle size, distribution
`(cid:129) Fines/oversize
`(cid:129) Particle shape
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`(cid:129) Solid form/polymorph
`(cid:129) Moisture content
`
`(cid:129) Particle size, distribution
`(cid:129) Fines/oversize
`(cid:129) Particle shape
`(cid:129) Cohesive/adhesiveproperties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Bulk/tapped/true density
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`
`(cid:129) Granule size and distribution
`(cid:129) Granule strength, uniformity
`(cid:129) Flow
`(cid:129) Bulk/tapped/true density
`(cid:129) Moisture content
`(cid:129) Residual solvents
`(cid:129) API polymorphic form or transition
`(cid:129) Purity profile
`(cid:129) Moisture profile (e.g. product
`temperature vs. LOD)
`(cid:129) Potency
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`
`(cid:129) Ribbon appearance (edge attrition,
`splitting, lamination, color, etc.)
`(cid:129) Ribbon thickness
`(cid:129) Ribbon density (e.g., envelop
`density)
`(cid:129) Ribbon porosity/solid fraction
`(cid:129) Ribbon tensile strength/breaking
`force
`(cid:129) Throughput rate
`(cid:129) API polymorphic form and transition
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`776
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`Pharmaceutical unit operation
`
`Table I. (continued)
`
`Yu et al.
`
`Input material attributes
`
`Process parameters
`
`Quality attributes
`
`(cid:129) Solid form/polymorph
`
`(cid:129) Roller temperature
`(cid:129) Fines recycled (yes or no, # of cycles)
`
`(cid:129) Particle size, distribution
`(cid:129) Fines/oversize
`(cid:129) Particle shape
`(cid:129) Cohesive/adhesiveproperties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Bulk/tapped/true density
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`(cid:129) Solid form/polymorph
`
`(cid:129) Particle size, distribution
`(cid:129) Fines/oversize
`(cid:129) Particle shape
`(cid:129) Melting point
`(cid:129) Density
`(cid:129) Solid form/polymorph
`(cid:129) Moisture content
`
`(cid:129) Particle/granule size
`and distribution
`(cid:129) Fines/oversize
`(cid:129) Particle/granule shape
`(cid:129) Cohesive/adhesive
`properties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Bulk/tapped/true density
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`(cid:129) Elasticity
`(cid:129) Solid form/polymorph
`(cid:129) Moisture
`
`(cid:129) Particle/granule size and
`distribution
`(cid:129) Fines/oversize
`(cid:129) Particle/granule shape
`(cid:129) Cohesive/adhesive properties
`(cid:129) Electrostatic properties
`(cid:129) Hardness/plasticity
`(cid:129) Bulk/tapped/true density
`(cid:129) Viscoelasticity
`(cid:129) Brittleness
`
`Extrusion–Spheronization
`(cid:129) Type of extruder (screw or basket)
`(cid:129) Screw length, pitch, and diameter
`(cid:129) Screw channel depth
`(cid:129) Screw blade configuration
`(cid:129) Number of screws (single/dual)
`(cid:129) Die or screen configuration (e.g., radial or axial)
`(cid:129) Die length/diameter ratio
`(cid:129) Roll diameter (mm)
`(cid:129) Screen opening diameter (mm)
`(cid:129) Screw speed (rpm)
`(cid:129) Feeding rate (g/min)
`(cid:129) Type and scale of spheronizer
`(cid:129) Spheronizer load level
`(cid:129) Plate geometry and speed
`(cid:129) Plate groove design (spacing and pattern)
`(cid:129) Air flow
`(cid:129) Residence time
`
`Hot melt extrusion
`(cid:129) Screw design (twin/single)
`(cid:129) Screw speed
`(cid:129) Screw opening diameter (mm)
`(cid:129) Solid and liquid feed rates
`(cid:129) Feeder type/design
`(cid:129) Feed rate
`(cid:129) No. of zones
`(cid:129) Zone temperatures
`(cid:129) Chilling rate
`
`(cid:129) Extrudate
`(cid:129) Density
`(cid:129) Length/thickness/diameter
`(cid:129) Moisture content
`(cid:129) API polymorphic form and transition
`(cid:129) Content uniformity
`(cid:129) Throughput
`
`(cid:129) Pellets after spheronization
`(cid:129) Pellets size and distribution
`(cid:129) Pellets shape factor (e.g. aspect
`ratio)
`(cid:129) Bulk/Tapped density
`(cid:129) Flow properties
`(cid:129) Brittleness
`(cid:129) Elasticity
`(cid:129) Mechanical strength
`(cid:129) Friability
`
`(cid:129) Extrudate density
`(cid:129) Length/thickness/diameter
`(cid:129) Polymorphic form and transition
`(cid:129) Content uniformity
`(cid:129) Throughput
`
`Tabletting
`(cid:129) Type of press (model, geometry, number of stations)
`(cid:129) Hopper design, height, angle, vibration
`(cid:129) Feeder mechanism (gravity/forced feed, shape of wheels,
`direction of rotation, number of bars)
`(cid:129) Feed frame type and speed
`(cid:129) Feeder fill depth
`(cid:129) Tooling design (e.g., dimension, score configuration,
`quality of the metal)
`(cid:129) Maximum punch load
`(cid:129) Press speed/dwell time
`(cid:129) Precompression force
`(cid:129) Main compression force
`(cid:129) Punch penetration depth
`(cid:129) Ejection force
`(cid:129) Dwell Time
`
`(cid:129) Tablet appearance
`(cid:129) Tablet weight
`(cid:129) Weight uniformity
`(cid:129) Content uniformity
`(cid:129) Hardness/tablet breaking force/
`tensile strength
`(cid:129) Thickness/dimensions
`(cid:129) Tablet porosity/density/solid fraction
`(cid:129) Friability
`(cid:129) Tablet defects
`(cid:129) Moisture content
`(cid:129) Disintegration
`(cid:129) Dissolution
`
`Encapsulation
`
`(cid:129) Machine type
`(cid:129) Machine fill speed
`(cid:129) Tamping Force
`(cid:129) No. of tamps
`(cid:129) Auger screw design/speed
`(cid:129) Powder bed height
`
`(cid:129) Capsule appearance
`(cid:129) Weight
`(cid:129) Weight uniformity
`(cid:129) Content uniformity
`(cid:129) Moisture content
`(cid:129) Slug tensile strength
`(cid:129) Disintegration
`(cid:129) Dissolution
`
`Eton Ex. 1037
`6 of 13
`
`

`

`Understanding Pharmaceutical Quality by Design
`
`777
`
`Pharmaceutical unit operation
`
`Input material attributes
`
`Process parameters
`
`Quality attributes
`
`Table I. (continued)
`
`(cid:129) Elasticity
`(cid:129) Solid form/polymorph
`(cid:129) Moisture
`
`(cid:129) Tablet dimensions
`(cid:129) Tablet defects
`(cid:129) Hardness/plasticity
`(cid:129) Density
`(cid:129) Porosity
`(cid:129) Moisture content
`
`(cid:129) Tablet dimensions
`(cid:129) Tablet defects
`(cid:129) Hardness/plasticity
`(cid:129) Density/porosity
`moisture content
`
`Pan coating
`(cid:129) Type of pan coater (conventional or side-vented)
`(cid:129) Pan (fully perforated or partial perforated)
`(cid:129) Baffle (design, number, location)
`(cid:129) Pan load level
`(cid:129) Pan rotation speed
`(cid:129) Spray nozzle (type, quantity, pattern, configuration,
`spray pattern)
`(cid:129) Nozzle to bed distance
`(cid:129) Distance between nozzles
`(cid:129) Nozzle orientation
`(cid:129) Total preheating time
`(cid:129) Inlet air flow rate, volume, temperature, dew point
`(cid:129) Product temperature
`(cid:129) Individual nozzle spray rate
`(cid:129) Total spray rate
`(cid:129) Atomization air pressure
`(cid:129) Pattern air pressure
`(cid:129) Exhaust air temperature, air flow
`(cid:129) Total coating, curing time and drying time
`
`Fluid bed coating
`(cid:129) Type of fluid bed coater
`(cid:129) Fluid bed load level
`(cid:129) Partition column diameter
`(cid:129) Partition column height
`(cid:129) Number of partition columns
`(cid:129) Air distribution plate type and size
`(cid:129) Filter type and orifice size
`(cid:129) Filter differential pressure
`(cid:129) Filter shaking interval and duration
`(cid:129) Spray nozzle (type, quantity, pattern, configuration)
`(cid:129) Nozzle port size
`(cid:129) Total preheating time
`(cid:129) Spray rate per nozzle
`(cid:129) Total spray rate
`(cid:129) Atomization air pressure
`(cid:129) Inlet air flow rate, volume, temperature, dew point
`(cid:129) Product temperature
`(cid:129) Exhaust air temperature, air flow
`(cid:129) Total coating, curing and drying time
`
`(cid:129) Size/dimensions
`(cid:129) Polymer type
`membrane thickness
`
`Laser drilling
`
`(cid:129) Conveyor type
`(cid:129) Conveyor speed
`(cid:129) Laser power
`(cid:129) Number of pulses
`(cid:129) Type(s) of lens(es)
`(cid:129) One or two sided
`(cid:129) Number of holes
`
`(cid:129) Coating efficiency
`(cid:129) Core tablet weight before and after
`preheating
`(cid:129) Moisture (gain/loss) during
`preheating
`(cid:129) Environmental equivalency factor
`(cid:129) Coated drug product (e.g., tablet or
`capsule) appearance
`(cid:129) % weight gain
`(cid:129) Film thickness
`(cid:129) Coating (polymer and /or color)
`uniformity
`(cid:129) Hardness/breaking force/Tensile
`strength
`(cid:129) Friability
`(cid:129) Moisture (gain/loss) during overall
`process
`(cid:129) Residual solvent(s)
`(cid:129) Disintegration
`(cid:129) Dissolution
`(cid:129) Tablet defects
`(cid:129) Visual attributes
`
`(cid:129) Coating efficiency
`(cid:129) Core tablet weight before and after
`preheating
`(cid:129) Moisture (gain/loss) during
`preh