Guidance for Industry 

The Use of Mechanical Calibration 

of Dissolution Apparatus 1 and 2 – 

Current Good Manufacturing Practice 

(CGMP) 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

January 2010 

Current Good Manufacturing Practices (CGMP) 
 

 

 

 

 

Guidance for Industry 

The Use of Mechanical Calibration 

of Dissolution Apparatus 1 and 2 – 

Current Good Manufacturing Practice 

(CGMP) 

Additional copies are available from: 

Office of Communication 

Division of Drug Information, WO51, Room 2201 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Ave. 

Silver Spring, MD 20993-0002 

Phone: 301-796-3400; Fax: 301-847-8714 

druginfo@fda.hhs.gov 

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

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

January 2010 

Current Good Manufacturing Practices (CGMP) 
Contains Nonbinding Recommendations 

TABLE OF CONTENTS 

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

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

III. RECOMMENDATIONS.................................................................................................. 3
 
 

 

 

Contains Nonbinding Recommendations 

Guidance for Industry1 

The Use of Mechanical Calibration 

of Dissolution Apparatus 1 and 2 – 

Current Good Manufacturing Practice (CGMP) 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if it satisfies the requirements of the applicable statutes and 

regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION 

This guidance is intended to aid drug manufacturers (including ancillary testing laboratories) in 

calibrating U. S. Pharmacopeia (USP) Dissolution Apparatus 1 and 2 to help assure that critical 

parameters associated with the dissolution apparatus meet certain mechanical calibration (MC) 

tolerances. 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, 

and vessel dimensions. 

 FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidance documents describe the Agency’s current thinking on a topic 

and should be viewed only as recommendations, unless specific regulatory or statutory 

requirements are cited. The use of the word should in Agency guidance documents means that 

something is suggested or recommended, but not required. 

1

 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug 

Administration (FDA). 

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Contains Nonbinding Recommendations 

II. BACKGROUND 

FDA’s current good manufacturing practice (CGMP) regulations require that laboratory 

apparatus be calibrated at suitable intervals in accordance with an established written program of 

scheduled procedures (21 CFR 211.160(b)(4) and 211.68). The enhanced MC procedure 

recommended in this guidance can be used as an alternative to the current Apparatus Suitability 

procedure for USP Dissolution Apparatus 1 and 2 described in USP General Chapter <711> 

Dissolution. The Chapter <711> Apparatus Suitability procedure requires that the dissolution 

apparatus assembly meet certain MC tolerances and that a performance verification test (PVT) 

be performed with specified USP Reference Standard (RS) tablets; however, the MC tolerances 

specified in USP <711> for the dissolution apparatus assembly are not as comprehensive or as 

stringent as those in the enhanced MC procedures recommended in this guidance. 

Recent studies performed in FDA and USP laboratories have identified several different sources 

of variation within Apparatus 1 and 2 that can be minimized by employing an enhanced MC 

procedure. In 1996, the Pharmaceutical Research and Manufacturers of America (PhRMA) 

Dissolution Committee formed a Subcommittee on Dissolution Calibration. In 2000, the 

subcommittee published a Stimuli article in the Pharmacopeial Forum in which it recommended 

“enhanced mechanical calibration” as a value-added means for maintaining dissolution apparatus 

in a state of calibration.2

 The use of an enhanced mechanical calibration procedure to satisfy the 

CGMP calibration requirement (§ 211.160(b)(4)) was endorsed by FDA’s Advisory Committee 

on Pharmaceutical Science (ACPS) on October 25, 2005,3

 following a presentation by FDA’s 

Center for Drug Evaluation and Research (CDER), Division of Pharmaceutical Analysis (DPA). 

DPA reported its findings from a gauge repeatability and reproducibility study showing that a 

significant amount of the observed variability in the dissolution test data was attributable to 

centering differences among the six dissolution vessels.4 In another study, DPA showed that 

vessel-to-vessel variability can be minimized by assuring that mechanical variables are 

controlled and by performing dissolved gas measurements to provide assurance of adequate 

deaeration of dissolution media before test samples are introduced.5 Subsequently, studies 

performed by USP using dissolution Apparatus 1 and 2 also identified several variables that 

contributed to the overall variation of the observed dissolution test results.6,7 These studies 

2

 PhRMA Subcommittee on Dissolution Calibration: Oates M, Brune S, Gray V, Hippeli K, Kentrup A et al., JulyAug 2000, Dissolution Calibration: Recommendations for Reduced Chemical Testing and Enhanced Mechanical 

Calibration, Pharmacopeial Forum; 26(4): 1149-1151. 

3

 Pharmaceutical Science Advisory Committee Meeting, October 25-26, 2005, transcript available at 

http://www.fda.gov/ohrms/dockets/ac/cder05.html#PharmScience. 

4

 Gao Z, Moore TW, Smith AP, Doub W, Westenberger B and Buhse L, 2007, Gauge Repeatability and 

Reproducibility for Accessing Variability During Dissolution Testing: A Technical Note, AAPS PharmSciTech; 

8(4): E1-E5. 

5 Gao Z, Moore TW, Doub WH, Westenberger BJ, Buhse LF, 2006, Effects of Deaeration Methods on Dissolution 

Testing in Aqueous Media: A Study Using a Total Dissolved Gas Pressure Meter, Journal of Pharmaceutical 

Science; 95(7): 1606-1613. 

6

 Eaton J, Deng G, Hauck W, Brown W, Manning R, Wahab S, 2007, Perturbation Study of Dissolution Apparatus 

Variables-A Design of Experiment Approach, Dissolution Technologies; 14(2): 20-26. 

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Contains Nonbinding Recommendations 

collectively helped to identify sources of significant variability that are within the analyst’s 

control. The published data show that dissolution variance within a lot of reference standard 

tablets can lead to the irreproducibility of dissolution measurements and contribute to 

uncertainty. Lack of sensitivity to variation and uncertainty hamper the ability of reference 

standard tablets to adequately calibrate dissolution apparatus. 

The collective published findings and outcomes from these studies lead FDA to conclude that 

sole reliance upon reference standard tablets to evaluate the performance of USP Dissolution 

Apparatus 1 and 2 does not provide assurance that the apparatus is adequately calibrated as 

required by CGMP regulations in § 211.160(b)(4). Enhanced MC is advantageous, enabling a 

dissolution apparatus operator to minimize the significant sources of measurement system 

variation identified in the recently published studies. 

We note that on August 1, 2007 (4th Interim Revision Announcement to USP 30), USP revised 

its General Chapter <711> Dissolution as follows: (1) removed the term calibrator tablets and 

replaced it with reference standard tablets to describe its Prednisone Tablets and Salicylic Acid 

Tablets and (2) retitled the <711> “Apparatus Suitability Test, Apparatus 1 and 2” to 

“Performance Verification Test, Apparatus 1 and 2.” In explaining these changes to Chapter 

<711>, USP stated that “USP’s RS tablets are not calibrator tablets – they are used in 

performance verification – and USP will no longer use the term calibrator to describe them.”7 

Subsequently, USP announced its intention as of December 1, 2009, to discontinue use of its 

Salicylic Acid Tablets RS (reference standard) in the Performance Verification Test for 

Dissolution Apparatus 1 and 2 in <711> (but it will retain its Prednisone Tablets RS).8 

In October 2007, USP posted to its Web site a toolkit to provide laboratories with an MC 

procedure, aligning with mechanical tolerances in <711> for the dissolution apparatus 

assemblies.9 However, neither the mechanical tolerances specified in USP <711> nor the MC 

procedure described in the USP toolkit are as comprehensive or as stringent as those in the 

enhanced MC procedure recommended in this guidance. 

III. RECOMMENDATIONS 

We recommend that an appropriately enhanced procedure for MC can be applied to USP 

Dissolution Apparatus 1 and 2 as an alternative procedure to meet CGMP calibration 

requirements (§ 211.160(b)(4)) . The calibration procedure should specify the frequency at 

7

 Deng G, Ashley AJ, Brown WE, Eaton JW, Hauck WW et al., 2008, The USP Performance Verification Test, Part 

I: USP Lot P Prednisone Tablets – Quality Attributes and Experimental Variables Contributing to Dissolution 

Variance, Pharmaceutical Research; 25(5): 1100-1109. 

8

 USP Proposes Changes to General Chapter <711> Dissolution, Pharmacopeial Forum; 34(5), September-October 

2008: 1243-1251. 

9 See USP Toolkit, Draft 5.1 October 2007, Section I. Mechanical Calibration, available on the Internet at 

http://www.usp.org/pdf/EN/dissolutionProcedureToolkit2007-10-04.pdf. 

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Contains Nonbinding Recommendations 

which each calibration step is to be performed. Calibration schedules should take into account 

the potential for variation in each parameter known to be critical. An example of an 

appropriately enhanced MC procedure is that used by CDER/DPA titled Mechanical 

Qualification of Dissolution Apparatus 1 and 2, available on FDA’s Web site at 

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf. This 

procedure describes the MC tolerances CDER/DPA uses in its laboratories to set up and maintain 

dissolution apparatus. Alternative methods of mechanical calibration can also be used to set up 

and maintain dissolution equipment, provided the chosen method is comparably enhanced to the 

FDA-recommended MC procedure so that mechanical variables that could significantly affect 

the accuracy and precision of test results are adequately controlled.10 Calibration procedures that 

rely solely on tests using reference standard tablets are generally not recommended, since they 

do not provide assurance that the apparatus is adequately calibrated, nor provide a reliable basis 

upon which to make precise tolerance adjustments to the dissolution apparatus. 

Either the Apparatus Suitability procedure in <711> or an appropriately enhanced MC method 

executed according to a written procedure will satisfy the CGMP requirement for calibration of 

laboratory apparatus and mechanical equipment for manufacturing, as set forth in §§ 

211.160(b)(4) and 211.68, respectively. For an approved drug product, the use of an alternative 

enhanced MC procedure instead of a performance verification test (e.g., USP <711> PVT) can 

be reported as a minor change in the applicant’s next annual report, consistent with 21 CFR 

314.70(d)(2)(vii). 

In addition to performing enhanced MC or the Apparatus Suitability procedure, manufacturers 

also should take appropriate measures to control the following recognized sources of significant 

variability in dissolution testing. 

1.	 Dissolved gases – Sometimes dissolved gases can cause bubbles to form around a dosage 

form undergoing testing, which can affect the results of a dissolution test.11 To eliminate 

this source of variability, the dissolution medium is degassed or deaerated. The USP 

degassing procedure (vacuum filtration at 41°C, then cooling to 37°C before use) can be 

time-consuming, so some laboratories use an alternative technique such as vacuum 

degassing with agitation at ambient temperature.12 Prednisone tablets are sometimes used 

as a reference standard to qualify the performance of these alternative degassing 

techniques. Instead, CDER/DPA uses a total dissolved gas pressure meter to accurately 

measure the amount of total dissolved gas in the medium. CDER/DPA recommends 

10 See also ASTM E 2503-07, Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus. 

11 Other factors that can influence dissolution results include (1) sampling probe size when automatic sampling is 

used; (2) method of tablet or capsule introduction into medium, including the use of sinkers (devices designed to 

make tablets or capsules sink to the bottom of the vessel); (3) basket construction (some vendors have clips to hold 

on the basket and others have o-rings); (4) vibration; and (5) accuracy of mechanical calibration procedures. 

12 Moore T, 1996, Dissolution testing: A Fast Efficient Procedure for Degassing Dissolution Medium, Dissolution 

Technologies; 3(2): 3-5. 

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degassing to less than 60 percent saturation of total dissolved gases at room
 

temperature.13
 

2.	 Vibration – There should be no significant vibration in the dissolution apparatus or 

medium. Some sources of vibration to guard against during apparatus installation and 

routine set up are: 

•	 the surrounding environment (HVAC, nearby equipment or operations) 

•	 the dissolution unit itself or one of its components 

•	 an external water bath circulating heater14 

3.	 Vessel dimensions – Vessel symmetry and other dimensional attributes may affect 

dissolution performance. Vessels should conform to USP <711> criteria for dimensions 

and tolerances and should be examined routinely for any irregular shape or defects.15 

13 Gao Z, Moore TW, Doub WH, Westenberger BJ, Buhse LF, 2006, Effects of Deaeration Methods on Dissolution 

Testing in Aqueous Media: A Study Using a Total Dissolved Gas Pressure Meter, Journal of Pharmaceutical 

Science; 95(7): 1606-1613. 

14 For additional detailed information on vibration sources and recommended criteria, see USP Toolkit, Draft 5.1 

October 2007, Section I. Mechanical Calibration, 1.2 Vibration, at 

http://www.usp.org/pdf/EN/dissolutionProcedureToolkit2007-10-04.pdf. 

15 For a list of vessel attributes that might influence results, see USP Toolkit, Draft 5.1 October 2007, Section I. 

Mechanical Calibration, 2.5.3 Vessel, at http://www.usp.org/pdf/EN/dissolutionProcedureToolkit2007-10-04.pdf. 

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