Notice: Guidance for Industry on the Use of Mechanical Calibration of 
Dissolution Apparatus 1 and 2--Current Good Manufacturing Practice; 
Availability

Federal Register: January 27, 2010 (Volume 75, Number 17)            
                  Page 4401-4402

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a guidance for industry entitled ``The Use of 
Mechanical Calibration of Dissolution Apparatus 1 and 2--Current Good 
Manufacturing Practice (CGMP).'' This guidance recommends an 
alternative method for manufacturers to comply with FDA's CGMP 
regulations that require laboratory apparatus be calibrated at suitable 
intervals in accordance with established written specifications. The 
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.

DATES: Submit written or electronic comments on agency guidances at any 
time.

ADDRESSES: Submit written requests for single copies of this guidance 
to the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, rm. 2201, Silver Spring, MD 20993-0002. Send one self-addressed 
adhesive label to assist that office in processing your requests. 
Submit written comments on the guidance to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://
www.regulations.gov. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Larry A. Ouderkirk, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 4228, Silver Spring, MD 20993-0002, 301-
796-1585.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``The Use of Mechanical Calibration of Dissolution Apparatus 1 
and 2--Current Good Manufacturing Practice (CGMP).'' The guidance 
recommends an alternative method for manufacturers to comply with the 
CGMP regulations that require laboratory apparatus be calibrated at 
suitable intervals in accordance with established written 
specifications (Sec. Sec.  211.160(b)(4) and 211.68 (21 CFR 
211.160(b)(4) and 211.68)).
    Historically, both MC and chemical (tablet) calibration procedures 
have been employed to assure that reproducible and repeatable data are 
obtained with dissolution test apparatus. Recent studies performed in 
FDA and USP laboratories have identified several significant sources of 
variation within Apparatus 1 and 2 that can be minimized by employing 
an enhanced MC procedure. The enhanced MC procedure recommended in the 
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 that employs basic MC with a 
performance verification test (PVT) using USP Reference Standard 
tablets.
    In the Federal Register of October 19, 2007 (72 FR 59298), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``The Use of Mechanical Calibration of Dissolution Apparatus 1 
and 2--Current Good Manufacturing Practice (CGMP).'' The notice gave 
interested persons an opportunity to submit comments by January 17, 
2008. Comments received during the comment period have been carefully 
reviewed, and changes were made to the draft guidance in an effort to 
make the document clearer. Also, as a result of the received comments, 
the guidance provides advice on controlling the following recognized 
sources of significant variability in dissolution testing: Dissolved 
gases, vibration, and vessel dimensions.
    In finalizing this guidance, FDA has made changes to the draft 
guidance to reflect the most recent changes to USP General Chapter 
<711> Dissolution. On August 1, 2007, USP revised its Chapter <711> as 
follows: (1) Changed the terminology ``calibrator tablets'' to 
``reference standard (RS) tablets,'' which is the term used to describe 
tablets used to establish system suitability; and (2) renamed the 
``Apparatus Suitability Test, Apparatus 1 and 2'' to ``Performance 
Verification Test, Apparatus 1 and 2.'' In making these revisions, USP 
has explicitly stated, ``USP's RS tablets are not calibrator 
tablets.''\1\ USP has also announced its intention as of December 1, 
2009, to discontinue use of its Salicylic Acid Tablets RS in the 
Performance Verification Test for Dissolution Apparatus 1 and 2 in 
<711> (but USP will retain use of its Prednisone Tablets RS). Although 
USP <711> establishes critical tolerances and parameters for 
dissolution apparatus, it does not describe enhanced MC practices that 
can optimize and assure consistent apparatus performance. In October 
2007, USP posted to its Web site a ``toolkit'' to aid practitioners in 
performing apparatus MC. However, we note that neither the mechanical 
tolerances specified in USP <711> nor the MC procedure described in the 
USP toolkit is as comprehensive or stringent as the enhanced MC 
procedure recommended in the agency guidance.
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    \1\ Deng G., A. J. Ashley, W. E. Brown, 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.
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    The CGMP regulations in Sec. Sec.  211.160(b)(4) and 211.68 require 
that laboratory apparatus (mechanical equipment used in manufacturing) 
be calibrated at suitable intervals in accordance with an established 
written program of scheduled procedures containing provisions for 
remedial actions. The enhanced MC procedure recommended in the agency 
guidance satisfies these CGMP requirements and thus can be used as an 
alternative to the Apparatus Suitability procedure described in USP 
<711>. Furthermore,

[[Page 4402]]

the agency does not consider a reference tablet-based procedure such as 
a PVT to be a critical component when the enhanced MC procedures 
recommended in the agency guidance are followed.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
agency's current thinking on a new process for making available to 
sponsors FDA guidance on how to design product-specific bioequivalence 
studies to support ANDAs. It does not create or confer any rights for 
or on any person and does not operate to bind FDA or the public. An 
alternative approach may be used if such approach satisfies the 
requirements of the applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http:/
/www.regulations.gov.

    Dated: January 21, 2010.
David Dorsey,
Acting Deputy Commissioner for Policy, Planning and Budget.
[FR Doc. 2010-1517 Filed 1-26-10; 8:45 am]
BILLING CODE 4160-01-S