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 
 
1 
Guidance for Industry  
 
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.  
 
 FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidance documents describe the Agencys 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 
 
FDAs 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 FDAs Advisory Committee 
on Pharmaceutical Science (ACPS) on October 25, 2005,3 following a presentation by FDAs 
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., July-
Aug 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 analysts 
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 USPs 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 FDAs 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 applicants 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 41C, then cooling to 37C 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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  Contains Nonbinding Recommendations 
 
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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