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)
TABLE OF CONTENTS
I.
INTRODUCTION
II.
BACKGROUND
III.
RECOMMENDATIONS
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.
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., 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.
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.
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.
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.