Quality by Design : Quality Target Product Profile & Critical Quality Attributes

Quality Target Product Profile (QTPP )
And
Critical Quality Attributes
Presentation prepared by Drug Regulations – a not for
profit organization. Visit www.drugregulations.org for
the latest in Pharmaceuticals.

www.drugragulations.org 1

Product Profile  Quality Target Product Profile (QTPP)

CQA’s  Determine “potential” critical quality attributes (CQAs)

Risk Assessments  Link raw material attributes and process parameters to
CQAs and perform risk assessment
Design Space  Develop a design space (optional and not required)

Control Strategy  Design and implement a control strategy

Continual  Manage product lifecycle, including continual
Improvement
improvement


Product Profile

CQA’s
 This presentation Part III of the
Risk Assessments series “QbD for Beginners” covers
basic aspects of
Design Space
◦ Quality Target Product Profile (QTPP) and
Control Strategy ◦ Critical Quality attributes.

Continual
Improvement


Dissolution ?

Dose ?

Appearance ?
Content
Uniformity ? Hardness ?


 The QTPP is an essential element of a QbD approach and
forms the basis of design for the development of the
product
 It describes the design criteria for the product, and should
therefore form the basis for development of the
◦ CQAs,
◦ CPPs, and
◦ Control strategy
 The QTPP provides an understanding of what will ensure
the quality, safety, and efficacy of a specific product for
the patient and is a starting point for identifying the CQAs.


A prospective summary of
the quality characteristics of
a drug product that ideally
will be achieved to ensure the
desired quality, taking into
account safety and efficacy of
the drug product : ICH Q8
(R2)


By beginning with the end in
mind, the result of development
is a robust formulation and
manufacturing process with an
acceptable control strategy that
ensures the performance of the
drug product


 Considerations for the quality target product profile could
include:
◦ Intended use in clinical setting, route of administration, dosage
form, delivery systems;
◦ Dosage strength(s);
◦ Container closure system;
◦ Therapeutic moiety release or delivery and attributes affecting
pharmacokinetic characteristics (e.g., dissolution, 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.


 For ANDAs, the target should be defined early
in development based on
◦ The properties of the drug substance (DS),
◦ Characterization of the RLD product and
◦ Consideration of the RLD label and
◦ Intended patient population


 The TPQP should only include patient relevant
product performance.
 For example, if particle size is critical to the
dissolution of a solid oral product, then the TPQP
should include dissolution but not particle size.
 Particle size would be a critical material attribute and
thus included in the process description and control
strategy.


 All product attributes to ensure equivalency of
safety and efficacy with respect to RLD.
 QTPP may change as more is available.
 Development report to contain evolution of QTPP
 End result is not final QTPP but
 An acceptable control strategy and regulatory
specification.
 For example, the final impurity and residual
solvent specifications may depend on the
properties of excipients used in the formulation.


Example from IWG Case Study: Sakura
case study
Quality Target Product Profile (QTPP)
Safety and Efficacy Requirements

ICH-GCG ASEAN, Kuala Lumpur, 26-28 July 2010 10
www.drugragulations.org

Quality Target Product Profile (QTPP)
Safety and Efficacy Requirements
Translation into
Characteristics /
Tablet Quality Target Product
Requirements
Profile (QTPP)
Dose 30 mg Identity, Assay and Uniformity

Appearance, elegance, size,
No off-taste, uniform color,
Subjective Properties unit integrity and other
and suitable for global market
characteristics
Acceptable hydrolysis degradate
Impurities and/or degradates levels at release, appropriate
Patient Safety – chemical purity
below ICH or to be qualified manufacturing environment
controls

PSD that does not impact
Patient efficacy – Acceptable API PSD
bioperformance or pharm
Particle Size Distribution (PSD) Dissolution
processing

Degradates below ICH or to be
Chemical and Drug Product Hydrolysis degradation &
qualified and no changes in
Stability: 2 year shelf life dissolution changes
bioperformance over expiry
(worldwide = 30ºC) controlled by packaging
period

ICH-GCG ASEAN, Kuala Lumpur, 26-28 July 2010

Quality Attribute Target Criticality
Dosage form Tablet, maximum weight 200mg Not Applicable

Potency 20 mg Not applicable

Pharmacokinetics Immediate release enabling Related to dissolution
Tmax in 2 hours or less
Appearance Tablet conforming to Critical
description shape and size
Identity Positive for acetriptan Critical

Assay 95 – 105% Critical

Impurities ACE12345 NMT 0.5%,other Critical
impurities NMT 0.2%, total NMT 1%
Water NMT 1% Not critical – API not sensitive
to hydrolysis
Content Uniformity Meets USP Critical

Resistance to 5-12kP Not critical since related to
Crushing (Hardness) dissolution


Quality Attribute Target Criticality
Friability NMT 1.0% Not critical

Dissolution Consistent with immediate release, Critical
e.g., NLT 75% at 30mins
Disintegration NMT 15mins Critical

Microbiology If testing required, meets USP Critical only if drug product
criteria supports microbial growth


 RLD : MR Tablets, 10 mg, IR & ER component , BCS class I
 NDA : 2009 in NDA “aaaaaa”
 Indications: Therapeutic relief, active ingredient Z that acts through
the CNS.
 Tablet MR was developed based on corresponding IR 3 mg
formulation , approved in 2005 in NDA “bbbbbb” ; and ANDA
approval for Example IR Tablets was (ANDA aaaaaa) was in 2010.
 Dosage: Once-a-day dosing
◦ Immediate onset of therapeutic relief similar to the IR product
◦ Maintenance of the therapeutic effect.
◦ 10 mg once daily in adults & a maximum daily dose of 20 mg.
◦ The tablet is scored to allow for 5 mg dosing,
 Elderly patients or
 Patients with hepatic insufficiency who do not clear the drug as rapidly
as normal


 The label warns of the potential risk of dose dumping that
may occur with the co-ingestion of alcohol.
 IR phase achieves plasma concentrations comparable to the IR
product (3 mg) through the first two hours for rapid onset of
the therapeutic effect.
 The ER phase sustains plasma concentrations of the drug
through 24 hours for maintenance of the therapeutic effect.
 The product label indicates that the drug can be taken
regardless of meals because there is no food effect.


QTPP Element Target Justification

Dosage Form MR Tablet Pharmaceutical equivalence
requirement: Same dosage form
Route of Administration Oral Pharmaceutical equivalence
requirement: Same route of
administration
Dosage Strength 10 mg Pharmaceutical equivalence
requirement: Same strength
Pharmacokinetics Fasting Study and Bioequivalence requirement
Fed Study
90 % confidence Initial plasma concentration through
interval of the PK the first two hours that provides a
parameters, AUC0- clinically significant therapeutic
2, AUC2-24, effect followed by a sustained plasma
AUC0-∞ and concentration that maintains the
Cmax, should fall therapeutic effect
within
bioequivalence
limits



Stability At least 24-month Equivalent to or better than RLD
shelf-life at room shelf-life
temperature
Physical attributes
Identification
Assay Pharmaceutical equivalence
Content Uniformity requirement: Meeting the same
Drug product quality compendial or other applicable
attributes Degradation products (quality) standards (i.e., identity,
Residual solvents assay, purity, and quality)
Drug release
Microbial Limits
Water Content


Container Closure System Suitable container HDPE bottles with Child Resistant
closure system to (CR) Caps are selected based on
achieve the target similarity to the RLD packaging. No
shelf-life and to further special protection is needed
ensure tablet due to the stability of drug substance
integrity during Z.
shipping
Administration/concurrence A scored tablet
with labeling can be divided into
two 5 mg tablets. Information is provided in the RLD
labeling
The tablet can be
taken without
regard to food (no
food effect).
Alternative methods of None
administration None are listed in the RLD labeling.


FDA Example :
QbD IR Tablet
Quality Target Product Profile
(QTPP)


 RLD : Acetriptan Tablets 20mg , BCS class II , IR uncoated Tablets
 NDA : NDA 211168 approved in 2000
 Indications: Therapeutic relief of moderate to severe symptoms.
 Dosage: One tablet twice a day
◦ Maximum daily dose of 40 mg.
◦ May be swallowed whole with a glass of water with or without
food.
 Well absorbed after oral administration.
◦ Tmax is 2.5 hours in patients.
◦ The mean absolute bioavailability is approximately 40%.
◦ The AUC and Cmax of are increased by approximately 8% to 12%
following oral dosing with a high fat meal.
◦ The terminal elimination half-life is approximately 4 hours.



Dosage Form IR Tablets Pharmaceutical equivalence
requirement: Same dosage form
Dosage Design Immediate release Immediate release design needed to
tablet without a meet label claims
score or coating
Route of Administration Oral Pharmaceutical equivalence
requirement: Same route of
administration
Dosage Strength 20 mg Pharmaceutical equivalence
requirement: Same strength
Pharmacokinetics Immediate release Bioequivalence requirement
enabling Tmax in
2.5 hours or less; Needed to ensure rapid onset and
Bioequivalent to efficacy
RLD



Stability At least 24-month Equivalent to or better than RLD
shelf-life at room shelf-life
temperature

Physical attributes
Identification
Assay Pharmaceutical equivalence
requirement: Must meet the same
Drug product quality Content Uniformity compendial or other applicable
attributes (quality) standards (i.e., identity,
Dissolution assay, purity, and quality).
Degradation products
Residual solvents
Water Content
Microbial Limits


Container Closure System Container closure Needed to achieve the target shelf-
system qualified life and to ensure tablet integrity
as suitable for this during shipping.
drug product.

Administration/concurrence Similar food effect RLD labeling indicates that a high fat
with labeling as RLD meal increases the AUC and Cmax by
8-12%. The product can be taken
without regard to food.
Alternative methods of None None are listed in the RLD labeling.
administration


Identity
POTENTIAL
QUALITY
ATTRIBUTES

Criticality assessment
Safety & Efficacy

• Appearance
Potency • Assay C
QTPP • Crystallinity
• CU Q
• Degradation A
• Disintegration s
• Dissolution
Purity • IR / MR
• Microbiology
• Sterility

Others


 A CQA is a physical, chemical, biological, or microbiological
property or characteristic that should be within an appropriate
limit, range, or distribution to ensure the desired product
quality. ICH Q 8 R2.
 From the perspective of product development, the FDA Office of
Generic Drugs further defines CQAs of drug products as those
that have the highest potential to be altered by formulation or
process variables. Therefore, these attributes should be
investigated in product and process development in order to
define an appropriate control strategy.
 CQAs are generally associated with the
◦ Drug substance,
◦ Excipients,
◦ Intermediates (in-process materials) and
◦ Drug product.


 CQAs of solid oral dosage forms are typically those
aspects affecting product purity, strength, drug
release and stability.
 CQAs for other delivery systems can additionally
include more product specific aspects, such as
◦ aerodynamic properties for inhaled products,
◦ sterility for parenterals, and
◦ adhesion properties for transdermal patches.
 For drug substances, raw materials and
intermediates, the CQAs can additionally
◦ include those properties (e.g., particle size distribution,
bulk density) that affect drug product CQAs.


 Drug product CQAs derived from the
◦ Quality target product profile and/or
◦ Prior knowledge
 The CQA’s are used to guide the product and process
development.
 The list of potential CQAs can be modified when the formulation
and manufacturing process are selected and as product
knowledge and process understanding increase.
 Quality risk management can be used to prioritize the list of
potential CQAs for subsequent evaluation.
 Relevant CQAs can be identified by an iterative process of quality
risk management and experimentation that assesses the extent
to which their variation can have an impact on the quality of the
drug product.


 All quality attributes are target elements of the drug
product and should be achieved through
◦ a good quality management system,
◦ appropriate formulation/process design and development.
 From the perspective of pharmaceutical
development, the subset of CQAs of the drug product
that also have a high potential to be impacted by the
formulation or process variables are investigated.
 Investigation culminates in an appropriate control
strategy.


 Accurate measurement of product attributes depends on the
capability analytical methodology.
 Analytical method should be assessed to determine the degree of
variability.
 Variability due to analytical method itself versus the degree of
variability inherent to the product.
 Use ANOVA-based statistical methods
 Quantitative discernment between different sources of variability
including,
◦ Instrument,
◦ Operator and
◦ Sample.
 Important for study of Product attributes as a function of
formulation and process parameters in a design of experiments
(DOE).


 Severity of harm (safety and efficacy) before
taking into account risk control;
 The rationale for distinguishing CQAs from
other quality attributes;
 Link to the patient as described in the QTPP;
 Basis on which the CQAs have been
developed (e.g., prior knowledge, scientific
first principles, and experimentation); and
 Inter-dependencies of the different CQAs.


• When the quality attribute
has an impact on the
patient. CQA
High Risk
• Efficacy: What if the patient
receives the wrong dose?
• Safety: What if the product
contains potentially harmful CQA/
degradants? QA QA
• Quality: What if the product
is damaged – will the
patient take it?
• Continuum of criticality – Low Risk QA
cascade from “critical” to
“not critical


Continual Improvement iteration

Potential
Impact to
QTPP Safety Non - Critical
Efficacy &
Quality?

Low Risk

Severity@ Critical
@ A Severity Scale is used to assess
relative magnitude of impact. A
change in criticality only occurs w/
a change in severity.
High risk


 Pharmaceutical development studies
 Technology transfer
 Manufacturing experience e.g.
 Internal and Vendor audits
 Raw material testing data
 Change management activities
 Stability reports
 Product Quality Reviews/Annual Product Reviews
 Complaint Reports; Adverse event reports; Recalls
 Trend data; Technical investigations
 Suppliers and Contractors
 Product history and /or manufacturing history


FDA Example :QbD MR Tablet


Quality Attributes of the Target Is it a Justification
Drug Product CQA?
Color and shape No Color, shape and appearance are not directly
acceptable to the linked to safety and efficacy. Therefore, they
are not critical. . The target is set to ensure
Appearance patient. No visual
patient acceptability
tablet defects
observed.
Odor No unpleasant odor No In general, a noticeable odor is not directly
linked to safety and efficacy, but odor can
affect patient acceptability and lead to
complaints. For this product, neither the drug
substance nor the excipients have an
unpleasant odor. No organic solvents will be
used in the drug product manufacturing
process
Physical
Attributes Size Similar to RLD Yes Tablet size correlates to swallowability;
therefore, it is critical. For comparable ease of
swallowing as well as patient acceptance and
compliance with treatment regimens, the target
for tablet size and volume is set similar to the
RLD.
Score and Scored and can be Yes The RLD tablet is scored and labeled for half-
Splitability split for half-dosing dosing; thus, ease of splitting is critical for this
drug product design.

Friability Not more than 1.0% No A target of NMT 1.0% mean weight loss is set
(whole and w/w according to the compendial requirement and
to minimize post-marketing complaints
split
regarding tablet appearance. This target
tablets) friability will not impact patient safety or
efficacy.

Drug Product CQA?
Identification Positive for drug Yes¹ Though identification is critical for safety and
substance Z efficacy, this CQA can be effectively controlled
by the quality management system and will be
monitored at drug product release.
Formulation and process variables do not
impact identity.
Assay 100.0% of label claim Yes Variability in assay will affect safety and
(whole and split tablets) efficacy; therefore, assay is critical.

Content Whole Conforms to USP Yes Variability in content uniformity will affect
Uniformity Tablet <905> Uniformity of safety and efficacy. Content uniformity of
whole and split tablets is critical.
Dosage Units
Split Tablet
Degradation Products Individual unknown Yes¹ The limit of degradation products is critical to
degradation product: drug product safety. The limit for individual
unknown degradation products complies with
NMT 0.2%
ICH Q3B. A limit for the total degradation
Total degradation products is set based on analysis of the RLD
products: NMT 1.0% near expiry. The molecular structure of drug
substance Z contains no functional groups with
obvious sensitivities to oxidation, hydrolysis,
acid, base, light or heat and its stability was
confirmed in a forced degradation study. No
chemical interactions were observed during the
development of the IR tablet (ANDA aaaaaa,
Section 3.2.P.2.1.2 and Section 3.2.P.8.3
(Appendix I)) or during the excipient
compatibility studies performed as part of the
development of the MR tablet. Therefore,
formulation and process variables are unlikely
to impact this CQA.

Drug Product CQA?
Residual Solvents Conforms to USP Yes¹ The drug substance and excipients used in the
<467> drug product formulation contain residual
solvents. The limit is critical to drug product
safety. However, no organic solvent is used in
the drug product manufacturing process and
the drug product complies with USP <467>
Option 1. This CQA will not be discussed in the
pharmaceutical development report but will be
considered when setting the raw material
acceptance criteria.
Whole Similar drug release The drug release profile is important for
tablets profile as RLD using a bioavailability (BA) and bioequivalence (BE);
therefore, it is critical. Since in vitro drug
predictive dissolution
release is a surrogate for in vivo performance,
method a similar drug release profile to the RLD is
targeted to ensure bioequivalence.
Split Similar drug release For tablets containing a multi-particulate
Yes system, a non-uniform distribution of beads
Tablets to whole tablets: f2 >
Drug may cause different drug release profiles
50
Release between whole and split tablets. Therefore, it is
critical and the target is set in accordance with
regulatory guidance.
Alcohol Comparable or lower The drug release profile in alcohol is critical to
Induced drug release patient safety. The target is set to ensure that
alcohol stress conditions do not alter
Dose compared to the RLD
bioavailability of the generic product and
Dumping in 5% (v/v), 20% (v/v), introduce additional risks to the patient
and 40% (v/v) Alcohol
USP in 0.1 N HCl
dissolution

Drug Product CQA?
Water Content Not more than 2.0% No Limited amounts of water in oral solid
w/w dosage forms will not impact patient
safety or efficacy. Therefore, it is not
critical.

Microbial Limits Meets relevant Yes¹ Non-compliance with microbial limits will
pharmacopoeia impact patient safety. However, as long as raw
materials comply with compendial microbial
criteria
requirements, the formulation and process
variables are unlikely to impact this CQA. Water
activity will be tested on the final prototype
formulation to confirm that the drug product
does not support microbial growth.

Yes¹:Formulation and process variables are unlikely to impact the
CQA. Therefore, the CQA will not be investigated and discussed
in detail in subsequent risk assessments and pharmaceutical
development.
However, the CQA remains a target element of the QTPP and is
ensured through the product and process design and the control
strategy


 For this product,
◦ Physical attributes (size and splitability),
◦ Assay,
◦ Content uniformity (whole and split tablets) and
◦ Drug release (whole tablets, split tablets and alcohol-induced dose
dumping)
 are identified as the subset of CQAs that have the potential to be
impacted by the
◦ formulation and/or process variables and,
 On the other hand, CQAs including
◦ Identity
◦ Degradation products and
◦ Microbial limits
 which are unlikely to be impacted by
◦ formulation and process variables
 will not be discussed in detail in the pharmaceutical development
report. However, these CQAs are still target elements of the QTPP
and are ensured through the product and process design and the
control strategy


FDA Example :QbD IR Tablet


Drug Product CQA?
Identification Positive for acetriptan Yes¹ Though identification is critical for safety and
efficacy, this CQA can be effectively controlled
by the quality management system and will be
monitored at drug product release.
Formulation and process variables do not
impact identity. Therefore, this CQA will not be
discussed during formulation and process
development.
Assay 100.0% of label claim Yes Assay variability will affect safety and efficacy.
Process variables may affect the assay of the
drug product. Thus, assay will be evaluated
throughout product and process development.
Content Conforms to USP Yes Variability in content uniformity will affect
Uniformity <905> Uniformity of safety and efficacy. Both formulation and
process variables impact content uniformity, so
Dosage Units
this CQA will be evaluated throughout product
and process development.
Dissolution NLT 80% at 30 Failure to meet the dissolution specification
minutes in 900 mL of can impact bioavailability. Both formulation
and process variables affect the dissolution
0.1 N HCl with 1.0%
profile. This CQA will be investigated
w/v SLS using USP throughout formulation and process
apparatus 2 at 75 development.
rpm


Drug Product CQA?
Degradation Products ACE12345: Yes Degradation products can impact safety and
NMT 0.5%, must be controlled based on compendial/ICH
requirements or RLD characterization to limit
Any unknown
patient exposure. ACE12345 is a common
impurity: NMT 0.2%, degradant of acetriptan and its target is based
Total impurities: on the level found in near expiry RLD product.
NMT 1.0% The limit for total impurities is also based on
RLD analysis. The target for any unknown
impurity is set according to the ICH
identification threshold for this drug product.
Formulation and process variables can impact
degradation products. Therefore, degradation
products will be assessed during product and
process development.

Residual solvents can impact safety. However,
no solvent is used in the drug product
manufacturing process and the drug product
complies with USP <467> Option 1. Therefore,
formulation and process variables are unlikely
Residual Solvents USP <467> option 1 Yes¹ to impact this CQA.


Drug Product CQA?
Water Content NMT 4.0% w/w No Generally, water content may affect
degradation and microbial growth of the
drug product and can be a potential
CQA. However, in this case, acetriptan is
not sensitive to hydrolysis and moisture
will not impact stability.

Microbial Limits Meets relevant Yes¹ Non-compliance with microbial limits will
pharmacopoeia impact patient safety. However, in this case,
the risk of microbial growth is very low because
criteria
roller compaction (dry granulation) is utilized
for this product. Therefore, this CQA will not
be discussed in detail during formulation and
process development.

Yes¹:Formulation and process variables are unlikely to impact the
CQA. Therefore, the CQA will not be investigated and discussed
in detail in subsequent risk assessments and pharmaceutical
development.
However, the CQA remains a target element of the QTPP and is
ensured through the product and process design and the control
strategy


 For this product,
◦ Assay,
◦ Content uniformity
◦ Dissolution and
◦ Degradation products
 are identified as the subset of CQAs that have the potential to be
impacted by the
◦ formulation and/or process variables and,
 Therefore, will be investigated and discussed in detail in subsequent
formulation and process development studies.
 On the other hand, CQAs including identity,
◦ Identity
◦ Residual solvents and
◦ Microbial limits
 which are unlikely to be impacted by
◦ formulation and process variables
 will not be discussed in detail in the pharmaceutical development
report. However, these CQAs are still target elements of the QTPP
and are ensured through the product and process design and the
control strategy

QbD Now Asks Sponsors to Define their Quality Target Product Profile (QTPP)

Asks whether Generic Firms are Focusing Product Design at the Right Target


Past / Present QbD Approach

ANDA QTPP: Guiding
Quality Surrogates
Formulation /
Used in the
process Development of the
submitted ANDA Formulation
without context and Process
Equivalent to the
RLD
Asks Sponsors How
Claimed to be
They Systemically
acceptable based
Arrived at a
upon a passing BE
Bioequivalent Drug
study to the RLD
Product
Bioequivalence by “Bioequivalence by
testing Design”


Is Formulation
Designed using a QTPP
that
Targets Equivalence to
the RLD?

Bioequivalence by design

Formulation designed based upon If QTPP Surrogate Does not Target
an understanding of critical quality Equivalence to the RLD, may Be
attributes to provide equivalent Acceptable. Sponsors Should
exposure profile needed to achieve Provide Justification Based On
equivalent clinical characteristics in Drug Pharmacokinetic and Clinical
Target patient population . Profile.


 Relationship between risk and criticality:
 Risk includes severity of harm, probability of
occurrence, and detectability, and therefore the level
of risk can change as a result of risk management.
 Quality attribute criticality is primarily based upon
severity of harm and does not change as a result of
risk management.
 The identification and linkage of the CQAs should be
considered when designing the control strategy.
 A well-developed control strategy will reduce risk but
does not change the criticality of attributes.


 CQAs can evolve throughout the product
lifecycle, for example:
◦ Change of manufacturing process
 change of synthetic route
◦ Subsequent knowledge gained throughout the
lifecycle
 raw material variability,
 pharmacovigilance,
 clinical trial experience, and
 product complaints


Product Profile  Quality Target Product Profile (QTPP)

CQA’s  Determine “potential” critical quality attributes (CQAs)

Risk Assessments  Link raw material attributes and process parameters to
CQAs and perform risk assessment
Design Space  Develop a design space (optional and not required)

Control Strategy  Design and implement a control strategy

Continual  Manage product lifecycle, including continual
Improvement
improvement


Quality by Design : Quality Target Product Profile & Critical Quality Attributes

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Quality by Design : Quality Target Product Profile & Critical Quality Attributes