02 November, 2017Moderated by Bryan Crist

Agilent Technologies

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USP<1058> Analytical Instrument QualificationIn this session we will discuss the “revised” USP chapter <1058> Analytical Instrument Qualification which became effective August 2017 in USP 40 First Supplement.

Although the bulk of the AIQ chapter remains unchanged we will review some of the expanded components in terms of processes, phases and risk management.

We will also discuss a re-definition of instrument performance qualification relative to its life cycle and its impact on the dissolution apparatus in the GMP laboratory.

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Welcome to the DDG Online Meeting• This is our 28th session

• Fourth and final meeting in 2017; now in our 7th year of consecutive meetings

• Worldwide users group for dissolution chemists

• Free, on-line, interactive bulletin board

• Provides annual and regional meetings around the world

• Place for practical answers to everyday questions on dissolution

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DDG Mission The mission of the Dissolution Discussion Group (DDG) is

to provide an independent forum to freely discuss the practical issues which challenge the pharmaceutical industry and affect the day-to-day task of developing, validating, and performing dissolution tests and related chemical analyses.

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www.dissolution.com

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Previous DDG Online Meetings: Aug 10, 2017 Dissolution Testing of Chewable Tablets May 11, 2017 USP Proposed Chapter <1236> Solubility Measurements Feb 09, 2017: Concepts for Qualifying Non-Compendial Dissolution Equipment Nov 10, 2016: USP Performance Testing of Ointments, Creams and Gels Aug 11, 2016: EMEA Draft – Reflection Paper on Dissolution Specifications for Generic Oral Immediate Release Products May 12, 2016: USP <1092> and its Impact on Dissolution Automation Feb 25, 2016: Dissolution SOP’s; Do What You Say and Say What You Do Nov 12, 2015: FDA Draft Guidance; Dissolution Testing and Specifications for BCS Class 1 and 3 Drugs Aug 13, 2015: Breaking Bad…Dissolution Habits May 14, 2015: Crosslinking of Gelatin Capsules and Dissolution Feb 12, 2015: Dissolution Method Development Considerations: Part 6 – Intrinsic Dissolution Nov 13, 2014: Dissolution Method Development Considerations: Part 5 – Alcohol Induced Dose Dumping Aug 14, 2014: Dissolution Method Development Considerations: Part 4 – Time Point Estimation May 15, 2014: Dissolution Method Development Considerations: Part 3 – Challenges for Poorly Soluble Compounds Feb 06, 2014: Dissolution Method Development Considerations; Part 2 – Media Volume and Sink Conditions for App 1&2 Nov 08, 2013: Dissolution Method Development Considerations; Part 1 – Filtration Requirements Aug 15, 2013: Operational Checks; Enhanced Mechanical Qualification Requirement - At Time of Use May 16, 2013: Deaeration of Dissolution Media; What’s All The Hot Air About?. Feb 14, 2013: Thinking Small - Challenges with Small Volume Dissolution Nov 15, 2012: Suggestions for the ASTM E2503-07 Dissolution Apparatus Mechanical Qualification; 5-Year Review Aug 16, 2012: Use of Enzymes for Dissolution Testing of Gelatin Capsules May 24, 2012: The Role of Dissolution in Quality by Design (QbD) Feb 16, 2012: The Dissolution Method Transfer Nov 17, 2011: The Dissolution Laboratory Audit Aug 18, 2011: Do f1 and f2 Tell the Whole Story? May 19, 2011: Best Practices for Success with the USP Dissolution Performance Verification Test (PVT) Mar 15, 2011: Mechanical Calibration: ASTM vs USP; Impact of ICH on Dissolution; QBD and PAT

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Today’s Panelists:

Bryan Crist – Agilent Technologies, Inc.

Ken Boda – Agilent Technologies, Inc.

Greg Martin - Complectors

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How USP <1058> Has Evolved

11/2/2017Agilent

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1. AAPS White Paper 2004

[From AAPS March 2003]

2. USP <1058> Aug. 2008

3. AAPS Round Table Nov. 2010

4. USP Stimulus Paper Jan. 2012

5. Proposed Draft <1058>

6. Draft USP <1058> Aug. 2013Bob McDowall & Chris Burgess

7. PF 41(3) June 2015

8. PF 42(3) May 2016

9. “New” USP<1058>

[Effective Aug. 2017]

AAPS = American Association of Pharmaceutical Scientists

Effective August 2017: “New” USP <1058> USP 40-NF 35 - First Supplement• “There are many ways of determining

that an instrument is qualified and under control, and these can include, qualification, calibration, validation, and maintenance.”

• “In order to ensure “fitness for purpose”, an integrated approach, based upon a risk assessment, is recommended”

• The USP is the only Pharmacopeia with a general chapter specific to Analytical Instrument Qualification (AIQ)

Changes are highlighted

11/2/2017Agilent

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“New” USP <1058> Summary

Components ofData Quality

Principles Apply to All Labs.

Explanation• Roles & Responsibilities• Software Validation• Firmware• Change Control• Documentation

AIQ ProcessQualification “Phases”

Risk Management by• Categorisation: A / B / C

Re-Definitionof the Life Cycle Process

A

Observe

B

Calibrate Qualify

C

Componentsof <1058>

11/2/2017Agilent

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New USP <1058> ComponentsAnalytical Instrument QualificationUser Requirement Specification (URS)

The first activity is the generation of a URS, which defines the laboratories’ specific needs along with technical and operational requirements that are to be met.

Key Messages:

Define laboratory needs

Requirements that must be met

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New USP <1058> ComponentsAnalytical Instrument QualificationDesign Qualification (DQ)

The DQ is the documented collection of activities that define the functional and operational specifications and intended purpose of the instrument. The DQ states what the laboratory wants the instrument to do.

Key Messages:

Defined functional and operational use.

Instrument must do what the lab wants

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New USP <1058> ComponentsAnalytical Instrument QualificationInstrument Qualification (IQ)

The IQ is the documented collection of activities necessary to establish that an instrument is delivered as designed and specified, is properly installed in the selected environment, and that this environment is suitable for the instrument.

Key messages:

Delivered as designed and specified

Properly installed

Environment is suitable

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New USP <1058> ComponentsAnalytical Instrument QualificationOperational Qualification (OQ)

The OQ is the documented collection of activities necessary to demonstrate that an instrument will function according to its operational specification testing in the selected environment. The OQ demonstrates fitness for selected use, and should reflect the URS*.

Key Messages:

Instrument Operational Specification performed in lab

Demonstrate fitness for purpose

Reflects the URS

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*Note: change to URS from DQ in previous <1058>

New USP <1058> ComponentsAnalytical Instrument QualificationPerformance Qualification (PQ)

The PQ is the documented collection of activities necessary to demonstrate that an instrument consistently performs according to the specifications defined by the user, and is appropriate for its intended use. After IQ and OQ have been successfully performed, the instruments continued suitability for its intended use is demonstrated through continued performance qualification.

Key Messages:

Specifications defined by the User

Document that instrument is appropriate for intended use

Demonstrated through continued and ongoing PQ

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PQ RequirementsPQ tests:

are based on typical on-site applications

are based on good science

reflect the intended use of the instrument

may be modular or holistic (dissolution eMQ or PVT)

may consist of analyzing known components or stds.

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PQ FrequencyThe testing frequency:

depends on the ruggedness of the instrument

depends on the criticality of the analytical method

may be scheduled at regular intervals, or unscheduled

with repeated test to compile performance history

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Preventive MaintenancePreventive maintenance:

is required at scheduled intervals

may include calibration (as found, as left and after PM)

plans and procedures must be documented

when PM fails;

the cause must be investigated and documented

the instrument must be maintained or repaired

the relevant OQ and PQ tests should be repeated

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Practices for PQ, change control and reviewDocument each PQ, maintenance and calibration activity.

Change control procedures required with changes in:

Instrument configuration

Firmware and software

Critical instruments should have periodic review to ensure that the system is still under control.

Instrument owner and management is responsible for PQ; although portions can be carried out by internal or external suppliers or service providers.

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NEXT: DISSOLUTION APPARATUS PERFORMANCE QUALIFICATION

Questions or comments about <1058>?

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The Dissolution Environment

In vitro dissolution data will be of great importance when assessing changes in production site, manufacturing process, or formulation, and assist in decisions concerning the need for bioavailability studies.

The proper qualification of the apparatus is critical to accurate and precise evaluation of dosage form performance

An Overview of the Dissolution Performance TestThe dissolution apparatus allows the testing of six dosage forms. Each position has:

An inert hemispheric vessel

A dissolution solvent (medium)

A rotating spindle which provides the hydrodynamic flow of the solvent across the surface of the dosage form

The dissolution apparatus must maintain these three components in terms of alignment, stability and isolation from the environment

Background of Performance QualificationUSP Performance Verification Test (PVT)

In existence since 1978

As of March 1st, 2010, a new set of acceptance criteria based on both geometric mean and %CV was adopted. The current lot is now lot R05990.

In addition to the changes in acceptance criteria, some minor changes to the dissolution test recommendations have occurred

Background of Performance Qualification

Note, this is not the current USP PVT lot.

Background of Performance QualificationFDA Concerns with USP PVT Prednisone Tablets:

Perceived variability with PVT Prednisone tablets not suitable for evaluating variability in the apparatus.

6-month qualification interval too long. High risk for failure which leads to Out-of-Specification (OOS) investigations.

Not keeping the apparatus “in tune” may lead to a false sense of security regarding calibration.

Difficulty meeting %CV Acceptance Criteria and values occasionally drift over time. Stability issues?

USP Performance Verification Test (PVT)Other concerns:

Expense of Tablets and RS. Down time.

When it fails, what was the cause?• Poor vessel quality and condition

• Poor paddle and basket quality and condition

• Vessel retaining systems failing

• Unvalidated deaeration techniques

• Unvalidated automated methods

• Unvalidated filters

• None of the above?

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Analytical Instrument QualificationUSP <1058> Analytical Instrument Qualification

Definition of Performance Qualification (PQ):

• Usually based on the instrument’s application and may consist of analyzing known components or standards

• PQ tests may be modular or holistic

• PQ tests should be based on good science and reflect the general intended use of the instrument

• When an instrument fails to meet PQ test specifications, it requires maintenance or repair

Dissolution Mechanical Qualification Guidance

The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 – Current Good Manufacturing Practice (CGMP)

FDA – Guidance for Industry January 2010

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070350.pdf

CGMP requires laboratory apparatus be calibrated at suitable intervals in accordance with established written specifications (21 CFR 211.160 (b)(4))

Dissolution Mechanical Qualification Guidance

The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 Current Good Manufacturing Practice (CGMP) - Claims:

Enhanced Mechanical Calibration (MC or MQ) of dissolution apparatus may be used as an alternative to the current Apparatus Suitabilityprocedure for Dissolution Apparatus 1 and 2 described in USP <711>

The MC procedure should specify the frequency at which each calibration step is performed

Either the USP procedure or an appropriate MC method executed according to a written procedure will satisfy the CGMP requirement for calibration of the laboratory apparatus…

Regardless of which procedure is used, appropriate measures must be taken to control the following sources of significant variability in dissolution testing: dissolved gases, vibration, and vessel dimensions.

Dissolution Enhanced Mechanical Qualification Standards

Mechanical Qualification of Dissolution Apparatus 1 and 2

US Food and Drug Administration (FDA), DPA-LOP.002, Version 2.0, Effective Date 02 June, 2006http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf

Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus

American Society for Testing and Materials, International (ASTM), Designation E 2503-13, Effective 2013

http://enterprise.astm.org/filtrexx40.cgi?+REDLINE_PAGES/E2503.htm

The 5 Steps for Implementation of Enhanced Mechanical Qualification of the Dissolution Apparatus

1. Check vessel, basket and paddle dimensions on receipt or obtain COC

2. Perform maintenance procedures recommended by manufacturer

3. Perform mechanical qualification: At documented intervals (6-month, 3-month, 1-month, weekly) based on risk

After apparatus is moved

After apparatus is repaired

4. Perform “Operational Checks” at each time of use

5. FDA requires implementation of laboratory controls for significant sources of vibration affecting dissolution testing• Vessel quality

• Deaeration

• Vibration

Dissolution MQ Standard Requirements#1 Check Dimensions Upon Receipt:

Paddle, Basket/Shaft, and Vessel apparatus components must be verified that they conform with the harmonized standard USP <711> Dissolution (USP, JP, EP)

Individual measurements for each dimension of each component must be documented

Certificates of Conformance (COC) may be obtained from Agilent to document conformance.

Otherwise, measurements must be documented by the end user.

#3 Mechanical Qualification Specifications &

Tolerances

Parameter ICH Harmonized(USP, JP, EP)

FDA DPA-LOP.002

ASTM E2503-07

USP Toolkit Ver 2.0

Basket and Paddle Depth

25 ± 2 mm 25 ± 2 mm 25 ± 2 mm(or <8%)

23-27 mm

Rotational Speed

± 4% of specified rate

± 2 rpm of target ± 2 rpm or within 2% of target (larger)

± 1 rpm of target

Shaft Wobble No significant wobble

≤ 1.0 mm total runout

≤ 1.0 mm total runout

≤ 1.0 mm total wobble

Shaft Verticality Not measured ≤ 0.5° from vertical

Within Bubble Not measured

Basket Wobble ± 1 mm ≤ 1.0 mm total runout

≤ 1.0 mm total runout

≤ 1.0 mm total wobble

Vessel/ShaftCentering

NMT 2 mm from center axis

≤ 1.0 mm from center line,2 pts upper and lower

≤ 1.0 mm from center line,2 pts upper and lower

NMT 2.0 mm difference (4-90°positions)

Vessel Verticality

Not Measured ≤ 1.0° from vertical (2 - 90°positions)

≤ 1.0° from vertical (2 - 90°positions)

NMT 0.5° from vertical

Vessel Plate Level

Not Measured Not Measured Not Measured NMT 0.5° from horizontal

Performance USP Prednisone Not Measured Not Measured USP Prednisone

Dissolution Mechanical Qualification Standard Requirements

#4 Operational Checks (document each time of use):

• Basket/shaft examination

• Paddle examination

• Vessel examination

• Vessel Temperature

• Vibration

Dissolution Mechanical Qualification Standard Requirements #5 FDA Control of significant sources

of variability:

Dissolved gases - to be removed through a validated deaeration procedure

Vibration - sources to be eliminated:

Shakers, mixers, fume hoods, pumps, centrifuge, radio, etc…

Malfunctioning internal components

Heater/circulator problems

Vessel dimensions - conform with cylindrical, circular sides and hemispherical bottom

The Advantage for MQ Time Savings (35-min vs 2-days with PVT)

Ease of use allows shorter qualification intervals

Data that helps you pinpoint possible problems

Now have the ability to trend parameter variation over time

No guesswork associated with manual and analog gauges

No standards or tablets to purchase

Provides instant failure investigation information

Reports exact information required by Enhanced MQ Standards

General Discussion

References United States Pharmacopoeial Convention, Inc. United States Pharmacopeia

(USP 40-NF 35). Rockville(MD); 2017:

<1058> Analytical Instrument Qualification

<711> Dissolution

FDA Guidance for Industry; The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 – Current Good Manufacturing Practice, January 2010

FDA Division of Pharmaceutical Analysis, DPA-LOP.002 Mechanical Qualification of Dissolution Apparatus 1 and 2, Ver. 2.0, June 2, 2006

ASTM E2503-13 Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus.

November 2, 2017Confidentiality Label38

Mark your calendars for the next Online DDG meeting:

Thursday, 08 February, 2018. Topic to be announced.

We look for your suggestions for current hot topics in the field of dissolution such as drug release from novel dosage forms, FDA Guidance, Apparatus Qualification, etc. We do want to hear from you so please continue to suggest topics at the DDG site www.dissolution.com .

Meetings are held quarterly on Tuesdays from 10:30-11:30 Eastern US Time. Please consult the DDG site for recorded sessions, future topics and updated information.

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www.dissolution.com

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