USFDA Draft Guidance on "Conditions: Reportable CMC Changes for Approved Drug and Biologic Products" Effective from 29 May 2015
INTRODUCTION:
This guidance has been developed to address the lackof clarity with respect to what chemistry, manufacturing, and controls (CMC)information in a marketing application constitutes an established condition ora "regulatory commitment" that, if changed following approval, requiresreporting to FDA. Clarification regarding which elements of the CMC informationconstitute established conditions and where in an application these elementsare generally expected to be described, should lead to a better understandingthat certain CMC changes can be made solely under the Pharmaceutical QualitySystem (PQS) without the need to report toFDA. For those changes that do require reporting, a better understanding of establishedconditions could allow for a more effective post-approval submission strategyby the regulated industry.
Specifically, this guidance describes those sectionsin a common technical document (CTD)-formatted application that typicallycontain information that meets the definition of established conditions, andprovides considerations for managing and communicating changes to the approvedestablished conditions over the lifecycle of an approved product.
Thisguidance is intended for applicants submitting original new drug applications (NDAs), abbreviated newdrug applications (ANDAs), and biologics license applications (BLAs) to CDERand CBER.
BACKGROUND:
The regulations at 21 CFR 314.50(d)(1) and 314.54(a)(1)require that any NDA or ANDA submitted to the Agency contain a CMC section thatdescribes information such as the composition of the drug product, manufactureof the drug substance, and manufacture of the drug product. Similarly, under 21CFR 601.2, applicants submitting BLAs must also provide relevant CMCinformation, such as a full description of manufacturing methods and data establishingstability of the product through the dating period.
All changes after approval of an application must bemanaged and executed in conformance with current good manufacturing practices(CGMP), although 21 CFR 314.70(a) and 601.12(a) only require a subset ofchanges to be reported to the FDA. 21 CFR 314.70(a)(1)(i) states that, otherthan the exceptions or alternatives provided in 21 CFR 314.70(a)(1)(ii), anapplicant must notify FDA about each change in each condition established in anapproved application beyond the variations already provided for in anapplication (i.e., an NDA or ANDA). Per 21 CFR 57 601.12(a)(1), an applicantmust inform FDA about each change in the product, production process, qualitycontrols, equipment, facilities, responsible personnel, or labeling establishedin the approved license application (BLA).
Afterapproval of an application, applicants desiring to make changes to this CMC informationmust evaluate the changes in the context of the regulations in order to determineif there is a need to report the change and associated supporting data andjustifications to FDA.
However,there has not been a common understanding of the meaning of the phrases "each conditionestablished in an approved application" and "established in the approvedlicense application(s)." The practical meaning of these phrases has beendescribed in many ways since the revision of the post-approval change regulationsas part of the Food and Drug Administration Modernization Act (FDAMA) in 1997.5 In recent communications,these phrases have been used synonymously with the term "regulatorycommitments" by both the regulated industry and the FDA. In this guidance, thephrases "conditions established in an approved application" and changes "establishedin the approved license application(s)" are referred to as establishedconditions, instead of "regulatory commitments" as there are varyinginterpretations of the term "regulatory commitment."
Althoughthe reporting mechanism for many CMC changes is clear, FDA is concerned that thereis confusion regarding which elements of an application are considered to beestablished conditions. This confusion could have a negative impact on changemanagement activities and could discourage continual improvement in productmanufacturing processes, lead to unnecessary submission of post-approval supplementsto FDA for changes that could be managed solely by a manufacturer's PQS, or,upon inspection, lead to Form 483 observations for changes that should havebeen reported to FDA. The recommendations in this guidance pertaining tosubmission of information about established conditions in originalapplications, supplements, and annual reports are intended to increase clarityand transparency and help avoid such potentially negative outcomes.
Additionally,better clarity regarding what parts of an application are established conditionsmight support a future approach in which an applicant could rely upon one ormore robust PQSs to assess, validate, and implement many post-approval changesappropriately, resulting in a more systematic reduction in or elimination ofcertain reporting requirements. Future guidance may be developed to furthersupport such an approach.
Thisdraft guide discussed about the following items:
ESTABLISHEDCONDITIONS
A. Definition of EstablishedConditions
B. Elements of a ControlStrategy that May Be Considered Established Conditions
PRINCIPLESFOR ESTABLISHED CONDITIONS IN APPLICATIONS
A. Sections of CTD ThatTypically Contain Established Conditions
B. Establishing Conditions asPart of the Application Submission and Review
C. Changes to EstablishedConditions
Further please refer this draft guide:
