AGILENT TECHNOLOGIESPRACTICAL SOLUTIONS NEWSLETTER

Volume 12, Issue 2

In This Issue:
Enhanced Mechanical
Qualification

1

Dissolution Qualification
Timeline / Schedule3

MQ Survey

4

MQ Guidance Summary

5

Dissolution 1-on-1

6

Enhancer Cell

7

Compendial Updates

7

l
a
i
c
e Q
p
S M onitidETransition to Enhanced Mechanical Qualification:
The Template
Making the transition to ASTM and FDA-approved enhanced Mechanical Qualification(MQ) procedures from the USP Performance Verification Test (PVT) is much more thansimply taking a few additional mechanical parameter measurements with tighter tolerances.
Agilent created the following template as a guide to ensure you have all the details on
the requirements. It is not as simple as eliminating Prednisone, but each of the suggested
practices must be established in the transition to enhanced MQ to ensure dissolution
apparatus integrity.
1. Verification of Dissolution Components
a. Measure/verify the dimensions of the vessels, baskets, and paddles upon receipt.
Component measurement and/or verification of a certificate “ensure the components
are appropriate for use1.”b. Ensure your Certificate of Analysis or Conformance (COA/COC) includes measurementsof each serialized component with appropriately documented measuring devices for thecritical parameters outlined in USP <711>. A Declaration of Manufacturing Conformity
certificate, without the individual component measurements or reference to a specificserial number, will not support the FDA or ASTM MQ guidance requirements.
2. Vital Dissolution Standard Operating Procedures (SOPs)
a. Operational Checklist - establish an ongoing evaluation procedure for component
integrity, to be implemented prior to and each time the dissolution apparatus is used.
Include the following details:
1. Inspect vessels, paddles, basket shafts and paddles2, ensuring cleanliness and proper
working condition.
2. Verify vessel temperature and monitor environment for influences of vibration.
3. Train dissolution analysts on procedure and MQ guidance for proper compliance.
Continued on p. 2

1

Enhanced MQ: continued

b. Preventative Maintenance Schedule - develop, implement anddocument the procedure based on recommendations of the
dissolution apparatus manufacturer, defining the frequency
based on usage.
1. Perform at 6- or 12-month intervals or based on a number ofspindle hours.
2. Verify the entire apparatus is evaluated, inspecting all parts
are in proper working condition.
3. Replace parts or components with compromised integrity to
avoid a future performance issue.
3. Enhanced Physical Parameter Measurements andTolerances

3. Shaft verticality: verify that each shaft is vertical at two
locations 90° apart
4. Vessel-to-shaft centering at 2 positions - one near the top
but below the vessel rim and one just above the bottom
portion of the vessel
4. Control of Significant Sources of Variability
a. Vessel Quality
1. Acquire and install quality vessels to avoid variation indissolution results caused by vessel imperfections.
2. It is recommended to use the same supplier for dissolution
vessels at all active vessel locations.
3. Review COA/COCs for minimal variability of USP tolerances.
Consider molded dissolution vessels to minimize variation,
where applicable.
4. Continually monitor and document vessel condition for
scratches, cracks and residue buildup.
b. Vibration
1. Place apparatus in an environment free from sourcesof vibration. Though the USP/FDA/ICH/FIP do not offer
tolerances for vibration, it may have a significant impact on
dissolution test results.

a. Verify the following measurements adhere to the tolerance
guidelines, with instructions on performing these measurementsin the ASTM Implementation Guidance2 and Agilent’s MQ
implementation white paper3.
1. Basket/paddle depth: 25 ± 2 mm
2. Rotational speed: within 2% or ± 2 RPM of target,
whichever is larger
3. Shaft wobble: ≤ 1.0 mm total runout
4. Shaft verticality: ≤ 0.5° from vertical
5. Basket wobble: ≤ 1.0 mm total runout
6. Vessel-to-shaft centering: ≤ 1.0 mm from center line
7. Vessel verticality: ≤ 1.0° from vertical at each point
b. Ensure that the position of the measurements conform to therequirements of the enhanced MQ procedures:
1. Shaft wobble: verify paddle and basket shaft wobble
measurements in addition to basket wobble.
2. Vessel verticality: measure in two locations on the vessel
wall, 90o apart.

2

2. Obtain baseline vibration measurements and periodicallycheck to monitor change over time to ensure the vibrationlevel of the environment remains suitable.
c. Dissolved Gases
1. Define, validate, and control degassing procedures fordissolution media to eliminate variability. This should be
performed as a part of testing SOPs with any dissolved
gasses that cause test interference.
2. Gently pour media and begin the test as soon as possible
following vessel filling to avoid reaeration.
References
1. E 2503-07 Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus; ASTM International; April 2007.
2. Implementation Guidance for American Society for Testing and Materials (ASTM) E
2503-07 “Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus.” The Open Drug Delivery Journal, 2010, Volume 4.
3. Agilent White Paper: Proper Implementation of Enhanced Mechanical Calibration of
Dissolution Apparatus 1 and 2, Boda and Crist, Agilent Technologies, May 2012.

Dissolution Qualification Timeline / Schedule
Physical parameter verification of the dissolution apparatus has
always been required before performing dissolution tests andperiodically as part of Performance Qualification testing. Oneof the advantages of enhanced Mechanical Qualification (MQ)
implementation is time savings. From a user perspective, these MQ
measurements may be performed in considerably less time whichallows them to be performed more often. Once the procedure
is firmly integrated into your laboratory routine, it provides
less downtime and scheduling issues. The time savings can besignificant with these hours, or even days, now available that used
to be filled with Prednisone testing and analysis.
Let’s explore how even greater efficiency and reduced instrument
downtime can be achieved. We’ll examine how some intermittent
procedures and monitoring can be inserted into the routine care andmaintenance of the dissolution equipment to prevent foreseeable
issues and help with future failure investigations.
The timeline displayed below offers one example of how
incorporating periodic evaluations – daily, weekly, monthly, or
quarterly – between traditional qualifications can lessen thelikelihood of problems related to your dissolution instruments. Dueto the ability to reduce measurement time and its software trending
feature, Agilent’s 280-DS Mechanical Qualification System(MQS) has been used to illustrate this concept. With routine
measurement and trending, the laboratory may see a problem
before a parameter is out of specification. For instance, steadily
increasing paddle wobble measurements from month to month
could be corrected before becoming an out-of-specification (OOS)
result.
The example timeline consists of an IQ/OQ/PQ (where PQ = USP
PVT) performed during initial qualification. Although the PVT is nolonger required if it has been replaced by full implementation of
MQ, it is still used by some dissolution laboratories during initialinstallation along with MQ as part of a hybrid approach. Overthe next 12 months, several shorter procedures are in place toconsistently monitor instrument performance and ensure apparatus

integrity:• Initial: IQ/OQ/PQ• Daily (or at time of use): Accessory examination per ASTM
E2503-07 guidelines. Verify any physical parameter as a check in only
minutes.
• Monthly: Abbreviated physical measurements; wobble for paddle,
basket shaft and basket along with vessel table level using the
280-DS, takes approximately 20 minutes to perform for both paddles
and baskets.
• Quarterly: Complete verification of physical parameters using
MQ procedure according to ASTM E2503-07; approximately 15-20
minutes per USP Apparatus using the 280-DS MQS.
• Biannually: Complete verification of physical parameters using
MQ procedures according to ASTM E2503-07; also includes
vibration measurement and re-verification of temperature probes; ifapplicable, auto-sampling instrumentation is inspected and reverified(e.g., volume accuracy); this procedure takes approximately 15-20
minutes per USP Apparatus and an additional 20 for temperature andvibration.
• Annually: Biannual procedure plus PM performed bymanufacturer.
• Intermittent: reverification of critical physical parameters
for failure investigation purposes of apparatus installed during
unexplained behavior; examination of data trends for the apparatus
approximately 15 minutes for complete measurement cycle using
280-DS. Additionally, environmental conditions are reevaluatedwhenever new instrumentation is added to the bench to ensure thatthe level and vibration parameters have remained unchanged.
The MQ procedure allows for a robust evaluation schedule to exist
with a very manageable time commitment. When coupled withthe 280-DS MQS and data trending capability of the software,
problems can be proactively addressed and failure investigations
improved dramatically. This is just one example of how you mayschedule your dissolution qualifications – for additional advice, chatwith your peers on the Dissolution Discussion Group (DDG) or
ask our in-house experts on the Dissolution Exchange.

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MQ Survey Results
Agilent surveyed the attendees from its recent MQ seminars and asked for their input on some of the key aspects of dissolution
qualification. Here’s what they said:
When considering changes to the dissolution
qualification schedule, what are or have been yourbiggest hurdles to overcome? *Risk assessment: will the new processeffectively identify problems

53%

Understanding of Regulations / Compliance

53%

Financial analysis / Justification

47%

Change Control process

47%

Implementation

24%* Participants were asked, if applicable, to enter multiple
answers.

4

What are the key factors that drive changes to your
Dissolution qualification schedule? *Regulatory compliance

77%

Time savings / Productivity

71%

Budget / Cost savings

41%

Continuous improvement

41%

Specifications / Tolerances of procedures

35%* Participants were asked, if applicable, to enter multiple
answers.

Mechanical Qualification Guidance Summary
One reason that many dissolution laboratories are hesitant to change their qualification procedure is due to a lack of understanding of
the position(s) taken by various worldwide agencies. The following table provides a brief summary and helpful links to describe somerecent guidance:
AgencyStatement (Excerpt)

International
Conference on
Harmonisation (ICH)”An appropriately rigorous mechanical calibration method, when properly executed, should satisfy the current
good manufacturing practice (CGMP) requirement for dissolution apparatus calibration under § 211.160(b)(4) ofTitle 21 of the Code of Federal Regulations.”
Reference: International Conference on Harmonisation ICH Guideline Q4B Annex 7 (R2) For Evaluation andRecommendation of Pharmacopeial Texts for Use in the ICH Regions on Dissolution Test – General Chapter;
European Medicines Agency, September 2010:

International
Pharmaceutical
Federation (FIP)“…the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument
should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If
additional system performance information is desired, a performance verification test using US Pharmacopeia
Reference Standard tablet or an established in-house reference product can be conducted. Any strict
requirement on the use of a specific performance verification test tablet is not recommended at this time.”
Reference: FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus

United States Food andDrug Administration(FDA)“This guidance recommends that an enhanced MC procedure (such as the one recommended in this guidance)
can be used as an alternative to the current Apparatus Suitability procedure for Dissolution Apparatus 1 and 2
described in USP General Chapter <711> Dissolution. Regardless of whether the enhanced MC procedure or
Apparatus Suitability procedure is used, the guidance also recommends that appropriate measures be taken
to control the following sources of significant variability in dissolution testing: dissolved gases, vibration, andvessel dimensions.”
Reference: FDA Guidance for Industry: The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 –Current Good Manufacturing Practice (CGMP): FDA Guidance for Industry: The Use of Mechanical Calibrationof Dissolution Apparatus 1 and 2 – Current Good Manufacturing Practice (CGMP)

United States
Pharmacopiea (USP)“Analytical instrumental qualification (AIQ), which includes installation qualification (IQ), operational
qualification (OQ), and performance qualification (PQ), is widely accepted. For dissolution assemblies,
the mechanical calibration steps in this guide should satisfy OQ and parts of IQ. PQ may be satisfied bya performance verification test (PVT), in support of which USP makes available official USP Prednisone
Reference Standard Tablets.”
Reference: USP Dissolution Toolkit Procedures for Mechanical Calibration and Performance Verification Test
Apparatus 1 and Apparatus 2 Version 2.0 March 22, 2010

World HealthOrganization (WHO)”Periodically verify the performance of the equipment3 utilizing an appropriate mechanical procedure orreference tablet.”
For example, use the mechanical process described in International Standard procedure ASTM 2503-07 orreference tablets such as those available from United States Pharmacopeia Convention Inc., every 6-12 months
for each individual system.
3

Reference: 5.5 Dissolution Test for Solid Oral Dosage Forms, Revised Draft Proposal; World HealthOrganization, July 20125

Dissolution 1-on-1: In-depth Training ina Self-paced Environment
The training and education of pharmaceutical chemists and analysts
is a vital component of regulatory compliance that helps to ensure
the safety of our pharmaceutical drugs. While there are many
courses available to teach HPLC and UV analytical techniques, ananalyst often learns dissolution techniques primarily by working
alongside another analyst. This method of training points out theimportant need for standardized dissolution training to ensure that
all analysts are capable of conducting accurate and reliable testingin a demanding laboratory environment.
To make it easier for analysts to get up-to-date dissolution training,
Agilent recently launched a newly updated version of Dissolution
1-on-1, its industry-leading, self-paced training course on the
Dissolution Exchange. This comprehensive online course isfree and can serve as a training resource for new analysts or asa refresher for experienced dissolution chemists, technicians,
reviewers, and metrologists.
This in-depth course provides six chapters of information as well
as a reference section and a comprehensive glossary of terms. It
incorporates many updates including the latest industry changes
regarding dissolution apparatus qualification, plus an introduction todissolution testing. The course covers:
Foreword
1. Introduction to Dissolution Testing
2. The Dissolution Apparatus - Anatomy
3. Critical Physical Parameters
4. Performing the Dissolution Test
5. Dissolution Apparatus Qualification
6. Dissolution and Automation
7. Reference Information
Information on Assessment and Certification
This globally-accessible resource is highly interactive and is an easy
to navigate learning experience. Simply register once and you’ll gain
access to a wealth of information to support your dissolution testing
training needs for a long time to come.

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Agilent has also partnered with CoAcS, Ltd. to produce acomprehensive assessment package that you can purchase to test
analysts on the course material. This testing package allows you
to identify managers by site or department that can in turn identify
those that need training and assessment. The training package
offers up to three opportunities for successful completion, at whichtime the user and his manager receive confirmation of satisfactorycompletion. Training packages are managed and tracked online foryour convenience.
Be sure to take a tour of the course to learn more. Or contact yourAgilent Representative today for detailed information on our training
resources.

Enhancer Cell and the new USP chapter<1724> Semisolid Drug Products –Performance Tests
The Enhancer Cell has been used by pharmaceutical industry forthe evaluation of ointments, creams,
gels and even selection of transdermal
components for nearly 20 years. It is
now contained as a performance test
for semisolid dosage forms in the First
Supplement to USP 36-NF 31, Official
August 1, 2013 as the “Immersion Cell
Apparatus, Model A”.
The new USP chapter provides detailed
theory on diffusion cell performance
testing with a variety of apparatus but
it highlights immersion cell apparatus
specifications and tolerances based on the Agilent Enhancer Celland the small volume adapter kit based on a 200-mL flat bottom
vessel and mini paddle. The Agilent Enhancer Cell and adapter
kit fits seamlessly in the Agilent 708-DS as well as all previous
instruments manufactured by Varian and VanKel. See the example
708-DS Enhancer Cell Conversion Kit details below.
For information on Agilent’s adapter kits for previous versionsof dissolution apparatus such as the 7000 or 7025 V-Series
Dissolution Apparatus, contact the Dissolution Hotline.
We also have a video available that illustrates proper Agilent
Enhancer Cell setup and technique.
PN

Description

Quantity

12-6368

TruAlign vessel conversion kit,
100/200 mL

6 or 812-5170

TruAlign vessel, flat bottom,
200 mL

6 or 813-3608

Mini paddle, lower
interchangeable, electropolishedstainless steel

6 or 812-4000

Enhancer Cell, 4 cm2 surface
area membrane

6 or 812-4020

Alignment tool, for 4 cm2
Enhancer Cell

1

12-4015

Adjustment tool, for all Enhancer
Cell sizes (Alternate sizes
available)

1Compendial Updates
Provided by:
Margareth R. C. Marques andWilliam Brown – U. S. Pharmacopeia
In an attempt to keep you abreast of any changes to the USP,
we’ve invited Margareth Marques and Will Brown from the USP toprovide an update.
Note: These are opinions and interpretations of the authors, and are not necessarily
the official viewpoints of the USP

Updates on USP Activities Related to Dissolution,
Disintegration, and Drug Release
All revisions and updates to any USP monographs or generalchapters are published in Pharmacopeial Forum (PF) for a 90-days
period for public comments. Pharmacopeial Forum is available
free of charge. The revisions are downloaded into the site every
two months. This site allows search by key word and by monographand general chapter titles. The online offering gives Pharmacopeial
Forum from volume 28 (Jan – Feb 2002) to the present.
Semisolid Drug Products Performance Tests
The new USP general chapter <1724> Semisolid Drug Products– Performance Tests is going to be official in the First Supplement
to USP 36 on August 1, 2013. This chapter covers the equipments(vertical diffusion cell, immersion cell, and cell for USP Apparatus 4)
and the procedures that can be used to evaluate the drug releasefrom semisolid drug products such as creams, ointments, gels andlotions. Currently, this test is not used routinely for batch release
but is an important tool during product development and for postapproval changes (see FDA Guidance for Industry – Nonsterile
Semisolid Dosage Forms – Scale-up and Post-approval Changes:
Chemistry, Manufacturing, and Controls; In vitro Release Testing
and In Vivo bioequivalence Documentation).
Development and Validation of Dissolution Tests
The USP general chapter <1092> The Dissolution Procedure:Development and Validation is under review and a revision is
being finalized for presentation in Pharmacopeial Forum. The
revised chapter will expand on the information currently provided
for method development and validation and will add sections on
automation, the analytical finish, and acceptance criteria includinginterpretation of results. Tentatively, the In Process Revision
proposal is targeted at PF 39(5) [Sept-Oct 2013].
Continued on p. 8

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Compendial Updates: continued

Drug Release <724>
When the USP general chapter <711> Dissolution was harmonizedwith the European Pharmacopoeia (EP) and the JapanesePharmacopoeia (JP), parts of the USP general chapter <724> Drug
Release were transferred to <711> Dissolution but the chapter<724> is not harmonized with EP and JP.
This chapter is being completely rewritten in a more user-friendly
way. The drawings of some of the equipments described in thischapter are being updated to better reflect what is commerciallyavailable. Also, new accessories are being added to the text. The
new version of the chapter will be published in PF 39(4) for publiccomments.
Dissolution Testing of Capsules
The new USP general chapter <1094> Liquid-filled Capsules –Dissolution Testing and Quality Attributes was published in PF 38(1).
After this publication comments were received saying that mostof the content of the chapter is applicable to all types of capsules.
As consequence of these comments, the chapter was completely
revised to include all types of capsules (hard or soft, gelatin or
starch or cellulose derivatives) and all types of capsule fill (liquid,
semisolid or solid). This chapter discusses the influence of capsuleshell composition, capsule fill formulation, storage conditions, etc.
on the dissolution behavior of capsules. Also, it contains informationon the dissolution testing conditions to be used with capsules withparticular emphasis on the use of enzymes with gelatin capsuleswith cross-linking. The new revised version of the chapter will be
published in PF 39(3).
Dissolution <711>
The USP general chapter <711> Dissolution contains a paragraphallowing the use of enzymes when gelatin capsules and gelatincoated tablets do not conform to the dissolution specification. The
chapter recommends the use of pepsin for dissolution media with a
pH of less than 6.8 and of pancreatin for media with a pH of 6.8 orgreater. The text in the chapter presents some challenges:
1. It does not relate the dissolution failure with the presenceof cross-linking in the gelatin. The user can assume that the
enzymes can be used for any type of failure, even those notrelated to gelatin cross-linking;8

2. Pepsin has an acceptable activity only up to pH around 4 andpancreatin with media with pH above 6.8. There is no enzyme
recommended for the gap in this pH range. Also, the chapter
does not give any guidance for dissolution media containing
surfactants. Pepsin and pancreatin are not compatible with some
types of surfactants.
To address all these issues, USP created an expert panel that isevaluating possible alternatives and modifications in the two-tierdissolution testing of cross-linked gelatin capsules. A revision to the
USP general chapter <711> Dissolution, together with the rational
for the modifications, will be published in a future issue of PF.
Please, contact Margareth Marques for more information.
The descriptions of dissolution apparatus given in general chapter<711> Dissolution differ from the enhanced mechanical calibration
specifications and information provided in the USP Dissolution
toolkit and by the FDA guidance, The use of mechanicalcalibration of dissolution apparatus 1 and 2—current
good manufacturing practice (cGMP). Opportunities forincorporating some of the enhanced mechanical calibration
specifications into the general chapter are being explored by theGeneral Chapters Dosage Forms Expert Committee. The Committee
recognizes their responsibility to avoid unilateral revision of thisharmonized general chapter. Therefore, in addition to the publiccomment process provided by Pharmacopeial Forum, any revision
will be through the processes of the Pharmacopeial Discussion
Group (European Pharmacopoeia, Japanese Pharmacopoeia, and
USP).
Workshop Dissolution Testing of Capsules
A workshop to discuss all the aspects of the dissolution testing of
any types of capsules, including dietary supplements, will be heldat the USP headquarters in Rockville, MD, USA on
March 24 – 25, 2014. The program and instructions for registration
will be available in the near future.

Updates on USP Activities Related to Dissolution,
Disintegration, and Drug Release
All revisions and updates to any USP monographs or generalchapters are published in Pharmacopeial Forum (PF) for a 90-day
period for public comments. Pharmacopeial Forum is available
free of charge online. The revisions are downloaded into thesite every two months. This site allows search by keyword and bymonograph and general chapter titles. Pharmacopeial Forum has
been available online since volume 28 (Jan – Feb 2002).
Ophthalmic Products
In the current version of USP there is only one chapter for
ophthalmic products, <771> Ophthalmic Ointments. This chapter
is out of date and addresses only ophthalmic ointments. This
chapter is being revised to include a discussion of all dosage forms
that can be applied to the eye. The revised chapter will incorporate
the quality tests appropriate for ophthalmic products and it is being
named <771> Ophthalmic Products – Quality Tests. The textof the general chapter <751> Metal Particles in Ophthalmic
Ointments has been transferred to <771> under Particulate andForeign Matter and its content has been updated. Therefore, thechapter <751> is being deleted. As a consequence of this change,
all monographs for ophthalmic ointments are being revised with thedeletion of the reference to chapter <751> and to other chapters
included in the new version of <771>. In place of the deleted
references, a new reference, Other requirements – meets therequirements under <771> Ophthalmic Preparations – Quality
Tests will be added.
A new general chapter, <1771> Ophthalmic Preparations –Performance Tests, discussing dissolution and drug release
testing for ophthalmic products has been developed. The newchapter discusses some of the apparatus and conditions that could
be use.

Workshop Ophthalmic Products
A workshop to discuss the new USP general chapters and othertopics related to ophthalmic products, including dissolution and drug
release, is going to be held at the USP headquarters in Rockville,
MD, USA on Oct 21-22, 2013. The program and instructions forregistration are available online. Please, contact Margareth
Marques for more information.
Workshop Dissolution Testing of Capsules
A workshop to discuss all aspects of the dissolution testing of any
types of capsules, including dietary supplements, will be held at the
USP headquarters in Rockville, MD, USA on March 24 – 25, 2014.
The program and instructions for registration will be available
online in the near future. Please, contact Margareth Marques
for more information.
Tablet Splitting
A new general chapter, <705> Quality Attributes of Tablets
Labeled as Having a Functional Score, has been developed.
The new general chapter gives specifications for tablets withlabeling approved by the FDA under the Guidance for Industry,
Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation.
Dissolution testing of split tablets from immediate release andextended release products is included as part of the new generalchapter.
The new chapter and a Stimuli article, explaining the proposed
requirements, will be published in PF 39(4), available online
July 2013. The deadline to send comments to Will Brown is
September 30, 2013.

Both chapters and a Stimuli article, with more information on
ophthalmic dosage forms, are going to be published in PF 39(5). The
deadline to send comments to Margareth Marques is November
30, 2013.

Learn more:

www.agilent.com/lifesciences/dissolution
The information is subject to change without notice.
© Agilent Technologies, Inc. 2013
Printed in the U.S.A., August 14, 2013
5991-2822EN

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