Controlled Correspondence Related to Generic Drug Development Guidance for Industry
Office of Communications,Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@https://www.doczj.com/doc/9d1078793.html,
https://www.doczj.com/doc/9d1078793.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2015
Generics
Controlled Correspondence Related to Generic Drug Development Guidance for Industry
Office of Communications,Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@https://www.doczj.com/doc/9d1078793.html,
https://www.doczj.com/doc/9d1078793.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2015
Generics
TABLE OF CONTENTS
I.INTRODUCTION (1)
II.BACKGROUND (1)
III.CONTROLLED CORRESPONDENCE (3)
A.Definition of Controlled Correspondence (3)
B.Additional Guidance on Inquiries Inside the Scope of Controlled Correspondence (3)
1.Controlled Correspondence Concerning Issues Raised in a Pending Citizen Petition, Petition for
Reconsideration, or Request for Stay (3)
2.Requests Related to Matters Still Under Consideration by the Agency (4)
C.Guidance on Inquiries Outside the Scope of Controlled Correspondence (4)
1.Exceptions to the Definition of Controlled Correspondence (5)
2.Topics Outside the Scope of Controlled Correspondence (6)
3.Entities Outside the Scope of Controlled Correspondence (7)
IV. SUBMITTING A CONTROLLED CORRESPONDENCE (7)
A.How to Submit a Controlled Correspondence (7)
B.Content of a Controlled Correspondence (8)
C.Additional Recommendations on the Content of Specific Types of Controlled
Correspondence Inquiries (9)
1.Requests Related to Inactive Ingredients (9)
2.Requests for Q1/Q2 Formulation Assessment (9)
3.Requests Requiring Review by More than One Discipline (10)
D.Controlled Correspondence Review Disciplines (10)
https://www.doczj.com/doc/9d1078793.html,RMATION ON COMMUNICATIONS FROM FDA TO REQUESTORS THAT SUBMIT CONTROLLED CORRESPONDENCE (11)
Guidance for Industry1
Controlled Correspondence Related to
Generic Drug Development
I. INTRODUCTION
This guidance provides information regarding the process by which generic drug manufacturers and related industry can submit correspondence to FDA requesting information related to generic drug development. This guidance also describes the Agency’s process for providing communications related to such correspondence. FDA is issuing this guidance as part of its implementation of the Generic Drug User Fee Amendments of 2012 (Public Law 112-144, Title III), commonly referred to as GDUFA.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances 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 guidances means that something is suggested or recommended, but not required.
II. BACKGROUND
On July 9, 2012, GDUFA was signed into law by the President.2 GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and to reduce costs to industry. The law is based on an agreement negotiated by FDA and representatives of the generic drug industry to address a growing number of regulatory challenges. GDUFA reflects input received during an open process that included regular public meetings, posting of meeting minutes, and consideration of comments from a public docket. Agreed-upon recommendations were sent to
1 The Office of Generic Drugs in the Center for Drug Evaluation and Research at the Food and Drug Administration prepared this guidance.
2 On October 5, 2012, the President signed into law the FDA User Fee Corrections Act of 2012 (Public Law 112-193). This act amended GDUFA so that due dates for GDUFA user fees in fiscal year 201
3 were not dependent on enactment of an appropriations act.
Congress, and Congress held hearings on GDUFA that included testimony from FDA, the generic drug industry, and other interested parties.
GDUFA requires that FDA and human generic drug manufacturers alike must meet certain requirements and commitments. Under GDUFA, FDA has agreed to specific program enhancements and performance goals, as set forth in the GDUFA Commitment Letter3 that accompanied the legislation. The GDUFA Commitment L etter included detail on FDA’s commitment to respond to questions submitted as “controlled correspondence” within certa in time frames. Specifically, the Agency agreed that:
?FDA will respond to 70 percent of controlled correspondence within 4 months from date of submission in fiscal year (FY) 2015.
?FDA will respond to 70 percent of controlled correspondence within 2 months from date of submission in FY 2016.
?FDA will respond to 90 percent of controlled correspondence within 2 months from date of submission in FY 2017.
?If the controlled correspondence requires input from the clinical division, one additional month will be added to the goals outlined above.4
The GDUFA Commitment Letter described controlled correspondence as follows: FDA’s Office of Generic Drugs provides assistance to pharmaceutical firms and related
industry regarding a variety of questions posed as “controlled docum ents.” See
[https://www.doczj.com/doc/9d1078793.html,/ForIndustry/UserFees/GenericDrugUserFees/ucm411122.htm].
Controlled correspondence does not include citizen petitions, petitions for
reconsideration, or requests for stay.5
This guidance provides additional detail and recommendations concerning: ?What inquiries FDA considers to be controlled correspondence for the purposes of meeting the Agency’s GDUFA commitment
?What information requestors can include in a controlled correspondence to facilitate FDA’s consideration of and response to a controlled correspondence ?What information FDA will provide in its communications to requestors that have submitted controlled correspondence
3 See Generic Drug User Fee Act Program Performance Goals and Procedures (GDUFA Commitment Letter) for fiscal years 2013 through 2017, available at
https://www.doczj.com/doc/9d1078793.html,/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf.
4 GDUFA Commitment Letter at 12. Any controlled correspondence submitted before October 1, 2014, does not fall under the time frames and goal dates identified in the GDUFA Commitment Letter. Notwithstanding, FDA intends to respond to those controlled correspondence as expeditiously as practicable.
5 GDUFA Commitment Letter at 15. We note that the Web page link quoted in the definition above has been updated to reflect the current link, because the link provided in the GDUFA Commitment Letter is no longer accessible.
Many of the recommendations in this guidance incorporate FDA’s historical practices in responding to controlled correspondence that were detailed on the Web page cited in the GDUFA Commitment Letter referenced above.6
III.CONTROLLED CORRESPONDENCE
A.Definition of Controlled Correspondence
As detailed in the GDUFA Commitment Letter, the aims of the generic drug user fee program include (1) ensuring the safety of generic drug products; (2) enhancing access by expediting the availability of these products; and (3) enhancing transparency by, among other things, improving FDA’s communications with and feedback to industry to expedite product access. Each of these goals is designed to directly benefit the public health. FDA and industry identified controlled correspondence in the GDUFA Commitment Letter as one mechanism to support these aims.
The GDUFA Commitment Letter did not provide a precise definition of controlled correspondence, however. The Agency thus has determined that the term should be further defined in a manner that best supports these principles. Accordingly, FDA defines controlled correspondence for the purposes of GDUFA as follows:
A correspondence submitted to the Agency, by or on behalf of a generic drug
manufacturer or related industry, requesting information on a specific
element of generic drug product development.
We believe that this definition encompasses the broad spectrum of issues that can arise as generic drug manufacturers and related industry (e.g., contract research organizations conducting bioanalytical or bioequivalence (BE) clinical trials, active pharmaceutical ingredient manufacturers, and excipient manufacturers) begin drug development that can benefit from targeted Agency consideration and, at the same time, helps to ensure that Agency resources supported by user fees are focused on facilitating and expediting development of generic drug products. Examples of topics that fall within and outside the definition are described in sections IV.C-D, below.
B.Additional Guidance on Inquiries Inside the Scope of Controlled
Correspondence
1.Controlled Correspondence Concerning Issues Raised in a Pending Citizen
Petition, Petition for Reconsideration, or Request for Stay
If a controlled correspondence is submitted that raises an issue that is the same as or related to an issue or question that is the subject of one or more pending citizen petitions, petitions for reconsideration, or requests for a stay, the goal dates set forth in the GDUFA Commitment Letter for controlled correspondence will apply from the date FDA issues responses to the pending
6 See Recommendations for Improving Submissions of a “Controlled Correspondence”to the Office of Generic Drugs, available at
https://www.doczj.com/doc/9d1078793.html,/ForIndustry/UserFees/GenericDrugUserFees/ucm411122.htm
petitions.7 Likewise, if a citizen petition, petition for reconsideration, or request for stay is submitted that raises an issue that is the same as or related to an issue or question in a pending controlled correspondence, the goal date for that controlled correspondence will apply from the date FDA issues a response to the related citizen petition, petition for reconsideration, or stay request.8 For example, if a controlled correspondence is submitted in FY 2015 that relates to an issue in a pending petition, and the Agency responds in FY 2016 to that petition, the 4-month goal date for FY 2015, the year in which the controlled correspondence was submitted, will apply to the controlled correspondence from the 2016 date that the petition is answered. FDA will notify the requestor if we determine that the controlled correspondence is the subject of or related to an issue or question raised in a citizen petition, request for reconsideration, or request for a stay. When the Agency issues the response, it will commence consideration of the controlled correspondence.
2.Requests Related to Matters Still Under Consideration by the Agency
FDA occasionally receives requests for information on issues that the Agency is considering, but for which no scientific or regulatory decision has been made or for which there is no clear clinical consensus. For a request for which controlled correspondence is the appropriate pathway but the subject is still under consideration at the time of the response goal date, FDA will notify the requester that the goal date has been missed because the request raised issues about which FDA has not made a decision. In such instances, the request will remain open until FDA issues a response.
3.Requests More Appropriately Addressed Through Other Mechanisms
In certain circumstances, the controlled correspondence mechanism may not be the optimal mechanism to gain FDA feedback on such a topic. For example, a pre-ANDA meeting that is more iterative in nature may provide a better forum in which to discuss certain issues, e.g., methods of characterization for complex products or clinically critical BE considerations. Other topics that are general in nature would be more appropriately considered as part of the Regulatory Science Initiative, e.g., the proposed use of in vitro data to support demonstration of BE for a new class of products. For such questions, the Agency will notify the requestor of the recommended alternative pathway and close the control.9
C.Guidance on Inquiries Outside the Scope of Controlled Correspondence
7 As set forth in the GDUFA Commitment Letter, controlled correspondence does not include citizen petitions, petitions for reconsideration, or requests for stay, even if they raise issues related to generic drug development (GDUFA Commitment Letter at 12).
8 FDA considers a controlled correspondence to be related to an issue or question that is the subject of a pending citizen petition if we determine that a decision regarding the issue or question raised in the citizen petition could affect our response to the controlled correspondence.
9 Controlled correspondence are intended to request information on a specific element of generic drug development, so they are not appropriate for requests that ask FDA to develop a new regulatory policy or change an existing policy. As described below, however, FDA intends to monitor subjects of controlled correspondence to consider issues for developing guidance documents.
1.Exceptions to the Definition of Controlled Correspondence
Historically, three types of inquiries fall within the above definition of controlled correspondence that FDA has treated differently from other inquiries on generic drug development: (1) requests for recommendations on the appropriate design of BE studies for a specific drug product (BE guidance requests); (2) requests for review of BE clinical protocols (clinical protocol requests); and (3) requests for meetings to discuss generic drug development prior to ANDA submission (pre-ANDA meeting requests). FDA will continue to respond to these inquiries consistent with its current practices, and to exclude these inquiries from the goal dates in the GDUFA Commitment Letter, as described below.
First, FDA will continue to address BE guidance requests consistent with the public process described in the A gency’s guidance for industry on Bioequivalence Recommendations for Specific Products.10 Under this approach, FDA publishes BE recommendations in product-specific guidances, the availability of which are announced in the Federal Register and are open to comment for a designated period. Before establishing this public process, FDA responded to requests for guidance on BE studies on an individual basis. Under that process, information about BE studies was only provided to those parties specifically requesting such information, and it created a significant burden on those FDA employees responsible for reviewing both the BE data in ANDAs and requests for recommendations on BE methodologies. The product-specific guidance process enhances transparency, provides a mechanism for public comment on recommended BE studies, and provides for more efficient use of Agency resources.
With this public process, FDA can be proactive in developing and publishing guidance for new drug products without waiting for inquiries on BE methodologies from individual requestors. As contemplated in the GDUFA Commitment Letter, this effort will also include guidance development resulting from the regulatory science initiatives funded by generic drug user fees. FDA anticipates that this process will continue to expedite the availability of BE methodologies to generic drug developers. This process involves time frames that differ from the goal dates for controlled correspondence, however, and the Agency has determined that it would not be appropriate to circumvent this public process by responding to individual requestors in order to meet the GDUFA goal dates for controlled correspondence. Parties may submit BE guidance requests for proposed products to GenericDrugs@https://www.doczj.com/doc/9d1078793.html,11 so that the Agency can continue to consider these requests in prioritizing BE guidance development.12
Second, FDA will continue to exclude clinical protocol requests from controlled correspondence, and the related goal dates. These are requests for review of clinical protocols for in vivo BE studies with pharmacokinetic, pharmacodynamic, or clinical end-point studies conducted to
10 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at
https://www.doczj.com/doc/9d1078793.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
11 This email address is a general OGD address to which certain submissions related to generic drugs may be submitted. This email address is monitored daily and submissions, including requests for BE guidance, pre-ANDA meetings, clinical protocol reviews, and controlled correspondence, are routed to the appropriate discipline or personnel.
12 We encourage requests for consideration of BE methods that modify or deviate from those proposed for a specific product to be submitted to the public docket of the particular product-specific BE guidance. As an alternative, the inquirer can submit such a request to GenericDrugs@https://www.doczj.com/doc/9d1078793.html, and it will be forwarded to the appropriate division. In addition, if a requestor wants clarification on a BE study recommended in the related product-specific draft guidance to support development of a generic drug product, the requestor can submit an inquiry as a controlled correspondence.
support demonstration of BE for a proposed generic product. Historically, FDA has not considered such requests as controlled correspondence, because these requests are more time- and resource-intensive than other requests and often call for consultation with multiple disciplines within the Office of Generic Drugs (OGD), as well as with other offices in the Center for Drug Evaluation and Research (CDER). Notwithstanding exclusion from the category of controlled correspondence for the purposes of GDUFA goal dates, we recommend that parties continue to submit clinical protocol requests to GenericDrugs@https://www.doczj.com/doc/9d1078793.html, so the correct discipline can review them promptly. FDA will respond to clinical protocol requests as expeditiously as practicable.
Third, FDA will not treat pre-ANDA meeting requests as controlled correspondence with related GDUFA goal dates, because such requests serve a different purpose than controlled correspondence and should include different information from an inquirer. The purpose of the controlled correspondence process is to provide a mechanism for a direct inquiry on FDA’s position with respect to a particular element of generic drug development, and for the Agency’s direct response. The purpose of a pre-ANDA meeting request, by contrast, is to seek a dialogue with the Agency on a particular matter for which the controlled correspondence process is not suitable. Similarly, materials and information submitted with a controlled correspondence should provide the Agency with the relevant information on which to base its considerations, while the materials submitted in support of a meeting request should help the Agency determine whether a meeting is appropriate. Accordingly, we will treat these meeting requests separately. Like BE guidance requests and clinical protocol requests, however, we recommend that parties continue to submit pre-ANDA meeting requests to GenericDrugs@https://www.doczj.com/doc/9d1078793.html, so the Agency can consider them expeditiously.
2.Topics Outside the Scope of Controlled Correspondence
This section provides additional guidance on the types of inquiries or topics that do not fall within the definition of controlled correspondence described above. First, the Agency considers any question related to a pending or approved ANDA a review issue. Such inquiries will not be treated as controlled correspondence and should be submitted only to the ANDA so they can be included as part of the full administrative record for that application.13
Second, inquiries that are submitted to FDA that are not directly related to generic drug development will not be considered controlled correspondence for the purposes of GDUFA. For example, inquiries requesting information on the administrative practices of OGD, or on development of generic products for which there has never been a U.S.-approved reference listed
13 The Agency will consider a request for information in a controlled correspondence regarding development of a new strength for a product for which the submitter is a sponsor of a pending or approved ANDA for other strengths. The Agency also will consider a request for information in a controlled correspondence regarding development of a different package configuration for a product for which the submitter is a sponsor of a pending or approved ANDA for other package configurations. For example, if an inquiry pertaining to a gel in a metered-dose pump is submitted and there is a pending or approved ANDA for gel in a unit-dose package, the controlled correspondence could still be accepted for review.
drug (RLD) identified in FDA’s Approved Drug Products with Therapeutic Evaluations (the Orange Book),14 will not be considered controlled correspondence.
Third, as reflected in the definition of controlled correspondence, FDA expects that a controlled correspondence will contain inquiries on a specific element of generic drug development, not general questions related to product planning. Consistent with FDA’s past practices, g eneral or insufficiently detailed questions related to product development are not the appropriate subject of controlled correspondence. For example, an inquiry seeking information on general approval standards for a particular product is not the appropriate subject of a controlled correspondence for the purposes of GDUFA. Likewise, an inquiry about the acceptability of an excipient without a proposed level for a specific RLD (which includes a specific product strength), or a question about the general acceptability of a particular device, provides insufficient detail for the Agency to respond. FDA provides information to stakeholders on its approval standards and general submission recommendations through FDA regulations and guidances.15 The controlled correspondence process is intended to facilitate, not supplant, the generic drug developmental endeavor.
3.Entities Outside the Scope of Controlled Correspondence
The controlled correspondence process, historically (and under the definition above), is available to generic drug manufacturers and related industry or their representatives, because this mechanism exists to facilitate generic drug development. Other parties (e.g., private citizens, financial firms, or public advocacy groups that are not directly involved in developing generic drug products) should submit their inquiries related to generic drugs to CDER’s Division of Drug Information.16
IV. SUBMITTING A CONTROLLED CORRESPONDENCE
A.How to Submit a Controlled Correspondence
Consistent with the agreement with industry described in the GDUFA Commitment Letter, requestors seeking FDA’s response to a controlled correspondence by the goal dates articulated in the GDUFA Commitment Letter (and listed above) should submit the correspondence electronically, via email to GenericDrugs@https://www.doczj.com/doc/9d1078793.html,.17 This will facilitate prompt consideration of and response to the controlled correspondence by the appropriate discipline. The email should be sent from a corporate email address. For this reason, we do not intend to consider emails generated from general, personal accounts as controlled correspondence.
14 An RLD is the “listed” (i.e., approved) drug that FDA has identified as the drug product upon which an applicant relies in seeking approval of its abbreviated application (21 CFR 314.3). RLDs are identified in the Orange Book and are available on FDA’s Web site at https://www.doczj.com/doc/9d1078793.html,/scripts/cder/ob/default.cfm.
15 FDA intends to monitor the subjects raised in controlled correspondence to identify future topics for Agency guidance.
16 See contact information for the Division of Drug Information on the second title page of this guidance.
17 Controlled correspondence that are not submitted electronically will be responded to, but will not receive a goal date. GDUFA Commitment at 7 (“Review metric goals […] only apply to submissions made electronically, following the e CTD format in effect at the date of submission”.)
FDA strongly discourages submitting controlled correspondence to individual FDA employees, and submitting additional copies of a controlled correspondence in paper form, by courier, or by facsimile. As described in section V below, FDA intends to provide requestors notification via email on the status of a request soon after it is submitted, which should provide a requestor adequate assurance that the Agency has received the communication. The Agency’s response will either state that FDA is considering the request as a controlled correspondence or provide the basis for not responding to it as a controlled correspondence, as described in this guidance.
B.Content of a Controlled Correspondence
FDA recommends the following information be included at the beginning of a controlled correspondence:
?Name, title, address, phone number, and entity (e.g., corporate affiliation) of the person submitting the controlled correspondence.
FDA intends to provide a response to the U.S. agent or representative of a foreign
company, similar to FDA practice when an ANDA is submitted. Please identify the
company for which you are the agent and include a copy of a letter of authorization with each controlled correspondence.18
?An email address to which a response to the controlled correspondence can be sent.
A requestor (or its U.S. agent) may apply for a secure email pathway by contacting
secureemail@https://www.doczj.com/doc/9d1078793.html,.
?The FDA-assigned control number and submission date of any previous, related controlled correspondence, if any, as well as a copy of that previous controlled
correspondence and F DA’s response, if any.
?Relevant RLD(s), as applicable, including application number, proprietary (brand) name, manufacturer, active ingredient, dosage form, and strength(s).
? A concise statement of the inquiry for which the controlled correspondence is being submitted.
? A recommendation of the appropriate FDA review discipline to review the controlled correspondence.
General information regarding review disciplines is provided in section IV.D, below.
?Relevant prior research and supporting materials.
FDA recommends that a requestor include in its controlled correspondence the pertinent prior research and supporting information on the specific element of generic drug
development about which it seeks information. If FDA determines, upon receipt of a
controlled correspondence, that the correspondence lacks sufficient information to
18 When possible, FDA recommends identification of the sponsor of the potential ANDA, which facilitates linkage
of the controlled correspondence to the ANDA when submitted.
consider the inquiry, it will notify the requestor of this deficiency and close the controlled correspondence. If FDA determines, during the substantive review of the inquiry, that the inquiry lacks sufficient information, it can either close the control at that time or contact
the requestor for additional information. If the Agency decides to close the control, it
will notify the requestor of that decision and the basis for that decision. If FDA contacts the requestor for additional information, the goal date period will be extended by the
amount of time that the Agency’s request for additional information is outstanding with
the requestor.
C.Additional Recommendations on the Content of Specific Types of Controlled
Correspondence Inquiries
This section provides additional recommendations for the content of specific types of inquiries submitted as controlled correspondence.
1.Requests Related to Inactive Ingredients
The Agency often receives requests for information pertaining to whether particular inactive ingredients present at higher levels than the maximums listed in the A gency’s Inactive Ingredient Database are permissible in a generic drug product. FDA recommends that a requestor submit for evaluation no more than three inactive ingredients, and under any circumstances no more than three proposed formulations total for a drug product at a given time. For example, a request that proposes three different ranges for a single inactive ingredient would be considered to include three proposed formulations, and a requestor should wait for FDA’s response to the controlled correspondence prior to submitting a different formulation for consideration. The Agency believes this is the reasonable limit based on what can be evaluated for a particular drug product within the GDUFA goal date period. This encourages sponsors to provide targeted submissions to the Agency, and allows firms to refine their subsequent formulation proposals based on FDA’s previous responses. In addition, such requests should include reference to a relevant RLD (including the specific drug product strength(s)) in order for FDA to evaluate the potential acceptability of an excipient in the context of a specific proposed drug product. Absent that information, there is no means for OGD to evaluate use of that inactive ingredient safely, which depends on many factors, including the conditions of use for the reference product. We note that FDA evaluates the ultimate acceptability of an excipient in the context of a specific proposed drug product formulation during ANDA review, when the Agency has the full complement of data and information in support of ANDA approval to consider.
Parties seeking to provide info rmation to update FDA’s Inactive Ingredients Database (for example, to correct information on FDA-approved products contained in the database or to provide data for FDA-approved products not in the database) should send such notifications to IIDUpdate@https://www.doczj.com/doc/9d1078793.html,. Such updates should not be submitted to GenericDrugs@https://www.doczj.com/doc/9d1078793.html,.
2.Requests for Q1/Q2 Formulation Assessment
For certain types of products, FDA’s reg ulations generally require that proposed products be qualitatively (Q1) and quantitatively (Q2) the same as the RLD with respect to inactive ingredients.19 In addition, FDA’s guidances sometimes recommend certain BE studies for drug products that are Q1/Q2 with respect to the RLD. When seeking review of proposed Q1/Q2
19 See, e.g., 21 CFR 314.94(a)(9)(iii).
formulations, we recommend the controlled correspondence include the following information (which can be found in the Orange Book):
?relevant RLD sponsor
?application number
?proprietary name
?active ingredient
?dosage form
?route of administration
?RLD approval date
?whether the product is prescription, over-the-counter, or in the “Discontinued” section of the Orange Book, which lists drug products that have been withdrawn from the market.
FDA recommends that no more than three proposed Q1/Q2 formulations of a single drug product be submitted in one controlled correspondence at a given time. Limiting a single control to no more than three formulation requests provides for FDA’s targeted an d timely review of such requests. In addition, the Agency recommends against submitting a request for evaluation of
Q1/Q2 and a separate request for evaluation of a proposed inactive ingredient at the same time. The formulation descriptions should include adequate details, including salt and hydration forms of the active ingredients and excipients.20
If a requestor is seeking formulation assessment for multiple drug products, FDA recommends that each request be submitted in a separate controlled correspondence. Thus, a requestor should not seek Q1/Q2 formulation assessment for generic products with different RLDs in a single controlled correspondence. This also includes separate formulation assessment requests for drug products with multiple strengths, because each strength is a separate drug product.
Consistent with the A gency’s past practice, FDA does not intend to review proposed formulations that are not required or FDA-recommended in guidance to be Q1/Q2 to the RLD. Non-Q1/Q2 formulations are permissible for certain products so long as the differences do not affect the safety or effectiveness of the product. The acceptability of such differences would be considered in the context of an ANDA review.
3.Requests Requiring Review by More than One Discipline
If a requestor seeks information related to separate elements of generic drug product development (e.g., information on proposed formulation and proposed product labeling), FDA recommends that the requestor submit separate requests regarding the product. This will facilitate timely review and response.
D.Controlled Correspondence Review Disciplines
This section provides additional information on the different disciplines that might review and respond to a controlled correspondence. In addition, this section provides examples of the types of inquiries a discipline might review. The Agency anticipates that this information will assist requestors in recommending the appropriate discipline to review a particular controlled correspondence, as suggested above. These descriptions are not intended to be exhaustive, and
20 To facilitate consideration of the request, FDA recommends that the inactive ingredient and/or the formulation information be presented in the format in which it would be submitted in an ANDA.
FDA has the discretion to determine which discipline should review and respond to a controlled correspondence.
?OGD’s Office of Bioequivalence
FDA anticipates that the Office of Bioequivalence will review correspondence containing inquiries related to the planning of BE studies. Within the Office of Bioequivalence, we anticipate that the Division of Clinical Review will review correspondence containing clear, concrete questions related to the planning of a BE study with clinical endpoints, and questions related to adverse events that occur during the conduct of a BE study. The Division of Clinical Review also reviews questions related to inactive ingredients.
?OGD’s Office of Research and Standards
FDA anticipates that the Office of Research and Standards will review correspondence containing questions, for example, on complex drug products or drug-device combination products.
?OGD’s Office of Operations, Division of Filing Review
We anticipate that the Division of Filing Review will review correspondence containing inquiries regarding FDA’s Inactive Ingredient Database and drug product formulation.
?OGD’s Office of Operations, Division of Labeling Review
FDA anticipates that the Division of Labeling Review will review, for example, correspondence regarding labeling standards for container/closure systems that are different from the RLD’s, and appropriate labeling differences.
?OGD’s Office of Generic Drug Policy
We anticipate that the Office of Generic Drug Policy, which includes the Orange Book staff, will review, for example, correspondence regarding patent listings or RLD questions.
?OPQ’s Office of Policy for Pharmaceutical Quality
FDA anticipates that the Office of Policy for Pharmaceutical Quality will coordinate OPQ’s review of correspondence amongst the sub-offices listed below. For example, OPQ will review correspondence containing inquiries regarding chemistry, manufacturing, and controls, as well as product quality microbiology for generic drugs. In addition, we anticipate that OPQ will review inquiries related to Type II drug master files for drug substances submitted in support of generic drug applications.
?OPQ’s Office of Lifecycle Drug Products
?OPQ’s Office of New Drug Products/Division of Lifecycle API and Division of Biopharmaceutics
?OPQ’s Offi ce of Process and Facilities
V. INFORMATION ON COMMUNICATIONS FROM FDA TO REQUESTORS THAT SUBMIT CONTROLLED CORRESPONDENCE
For inquiries submitted to GenericDrugs@https://www.doczj.com/doc/9d1078793.html,, FDA will provide the following information to a requestor regarding its receipt and consideration of the inquiry.
Upon receipt of a submission, FDA will evaluate whether the submission will be considered a controlled correspondence for the purposes of GDUFA. FDA then will send the requestor one of two emails: (1) an email confirming acceptance of the submission as a controlled correspondence for the purposes of GDUFA, which will include a controlled correspondence tracking number; or (2) an email informing the requestor either that the Agency does not consider the submission a controlled correspondence and the basis for that decision, or that FDA lacks adequate information to make this determination. In most instances, we anticipate confirming acceptance of the submission within seven calendar days, which communication will contain a receipt date that the requestor can use to calculate the goal date. If a requestor resubmits a request for information that addresses any problem that FDA identified with a previous request, the Agency will consider this a new controlled correspondence and process it as such.
After reviewing the request for information in the controlled correspondence, FDA will respond in written form via email to the email address from which the original controlled correspondence was sent. The length and content of FDA’s response will depend on the nature of the inquiry submitted. We intend that the comments we provide in response to a controlled correspondence will be comprehensive as of the date of the response. We note that response comments represent the Agency’s current thinking on a topic at that time, and that our scientific thinking may evolve in the future.
FDA will not respond to status requests regarding pending controlled correspondence prior to the goal date.21 If the Agency does not respond to the controlled correspondence by the goal date, we will send an acknowledgement to the requestor with notification that the request is still under consideration.
We recognize that upon receipt of FDA’s response to a controlled correspondence, requestors might have follow-up questions or wish to request related, additional information. Because Agency staff would have to expend resources to review and respond to these follow-up questions and requests for additional information, FDA will treat the requests as new controlled correspondence. This ensures that the follow-up question is tracked and that all requestors are treated equitably. In these instances, we recommend that a requestor submit a new controlled correspondence and include the controlled correspondence tracking number(s) of the previous inquiry to facilitate FDA’s review and response.
21 For pre-FY 2015 controlled correspondence, OGD will strive to respond to these controls as expeditiously as practicable.
仿制药一致性评价 This model paper was revised by the Standardization Office on December 10, 2020
仿制药一致性评价 定义 仿制药一致性评价是指对已经批准上市的仿制药，按与原研药品质量和疗效一致的原则，分期分批进行质量一致性评价，就是仿制药需在质量与药效上达到与原研药一致的水平。药学研究是指通过体外溶出等分析方法对药物进行药学分析，其目的在于考察制剂的生产工艺及处方是否有需要变更，初步确认制剂与原研药的一致性。 生物等效性（bioequivalency , BE ）是指在同样试验条件下试验制剂和对照标准制剂在药物的吸收程度和速度的统计学。当吸收速度的差别没有临床意义时，某些药物制剂其吸收程度相同而速度不同也可以认为生物等效。 一站式服务 我司作为提供专业的医药科技公司，能够提供包括： 1、药学研究（CMC）：包括：制剂处方工艺、质量研究（杂质及溶出曲线等）、稳定性考察等完整的药学研究过程 2、生物等效性（BE）：包括：寻找合作临床机构、招募受试者采血、生物样品测试及分析、数据管理及统计分析等全过程的服务 3、需要进行大临床试验的品种，按照2017年已经颁布的指导原则，参照Ⅱ期、Ⅲ期临床试验的经验，提供整个临床试验的组织及监查管理服 一致性评价（CMC&BE）的主要工作内容 第一阶段：项目评估
◆项目的市场价值 ◆竞争品种的多少 ◆是否有参比制剂 ◆评估需要的费用和周期 ◆咨询相关官员与专家 ◆项目立项确定进行 BCSⅠ类或者Ⅲ类豁免BE的申请：高渗透性的数据与文献支持材料、体外溶出曲线数据的提供与分析，如果能够满足CFDA的2016年87号文《人体生物等效性试验豁免指导原则》就可以豁免BE研究。 第二阶段：药学研究（CMC） ◆参比制剂的选择及备案 ◆购买参比制剂 ◆与参比制剂的质量对比（主要包含溶出曲线和杂质） ◆药学等效判定 ◆处方工艺等的二次开发 ◆溶出曲线的对比 ◆处方工艺的确定及中试放大
刚刚！！发布仿制药一致性评价现场检查-企业指南 为规范仿制药一致性评价现场检查工作，持续提高检查工作质量和效率，在原国家食品药品监督管理总局仿制药质量和疗效一致性评价相关文件的框架下，核查中心组织起草了《企业指南：质量和疗效一致性评价仿制药品药学研制现场检查要求》和《企业指南：质量和疗效一致性评价仿制药品生产现场检查要求》，现向社会公开征求意见。请于2018 年5 月3日前将有关意见或建议以电子邮件形式反馈至核查中心。真诚感谢一直以来对我中心工作的支持。原国家食品药品监督管理总局食品药品审核查验中心（暂）2018 年4 月2 日企业指南：质量和疗效一致性评价仿制药品药学研制现场检查要求（草案） 一、前言为保证开展质量和疗效一致性评价的仿制药品药学研制现 场检查工作的质量和效率，特制定本要求，本指南仅代表食品药品审核查验中心目前对相关事宜的考虑，将根据对检查工作的政策要求适时进行调整。本指南所提及的仿制药具体指：化学药品新注册分类实施前批准上市的需开展一致性评价的仿制药。本指南所指的检查要求主要包括：申请人在接受现场检查时，需提前准备的与产品注册、研制现场相关的资料和人员要求。 二、资料要求 （一）首次会议企业汇报资料首次会议需要生产企业以幻灯片的形式介绍如下内容：药品研制基本情况（如属委托，应说明被委托研究单
位基本情况）。 研制所涉及的批次（含批）批量用途，研制批次（含批）生产的地址、生产线、时间地点、使用量和剩余量等。研制批次（含批）所用处方生产工艺、原辅料包装材料来源及标准、生产线（设备设施）、产品质量标准（含中间控制标准）等是否与已上市/拟上市商业化生产规模的批次一致。参比制剂的来源、采购和使用情况。药品和参比制剂体外研究的对比研究情况，研究时间、批号和研究结果 药品关键质量属性（含稳定性）研究情况。 （二）检查时需事先准备的文件（尽可能提供原始文件）接受现场检查品种仿制药质量和疗效一致性评价全套注册申报资料。 委托研究协议和质量协议，如有。参比制剂的来源及证明，如购买发票、赠送证明等。参比制剂的包装标签、说明书、剩余样品等。参比制剂的接收、发 放、使用记录或凭证。 药品相关研究记录，包括：* 处方工艺研究原始记录，如有；* 样品试制相关原始记录；* 质量研究相关原始记录；* 体外评价及稳定性研究的相关原始记录；* 仪器设备使用记录；* 纸质图谱及电子图谱。药品检验方法确认或验证资料。 稳定性试验方案及报告。体外研究总结报告。 溶出度仪的验证资料。研究用的剩余样品情况（不应销毁）。 三、人员要求与药物研制相关工作人员应在岗配合检查工作，包括：
合规性评价管理制度 （WHNYLM/ZD-115-2015） 第一章总则 第一条为规范合规性评价管理，依据集团《煤化工企业安全风险预控管理体系要求》及能源公司相关规定，结合公司实际，制定本制度。 第二条本制度规定了合规性评价的计划、方法、范围和不符合的管理要求。 第三条本制度中所称的合规性评价是指企业或者组织为了履行遵守法律法规要求的承诺，以定期评价对适用法律法规的遵循情况的一项管理措施。 第四条合规性评价遵循以下原则： （一）公平公正，全面开展； （二）基于事实和数据而定。 第五条本制度适用于公司各部室及三厂一矿（以下简称各单位）。 第二章组织与职责 第六条党群工作部是合规性评价的主责部门，主要职责： （一）负责法律法规及其他要求的获取、识别； （二）负责编制年度合规性评价计划； （三）明确合规性评价的方法； （四）组织开展合规性评价工作；
（五）编制公司合规性评价报告； 第七条对评价的各单位不符合，各单位制定纠正措施和预防措施。 第八条安健环部负责将监督、检查过程中发现的不符合法律法规的项目报送至党群工作部，做为合规性评价的依据。 第三章合规性评价的方法 第九条通过审核对照已识别的法律、法规和其他要求进行合规性评价； 第十条通过对文件和记录进行评审评价； 第十一条通过对现场、资料等的检查评价； 第十二条通过和有关人员面谈评价； 第十三条通过委托第三方评价； 第十四条通过监测和测量对安全、健康和环境影响的关键特性进行评价； 第十五条通过体系内部审核评价。 第四章合规性评价的依据 第十六条依据识别适用的法律、法规和其他要求。 第十七条依据有关的监测数据： （一）环境监测报告； （二）现场职业卫生监测报告； （三）职业危害岗位体检报告；
序号重要环境 因素 法律法规和其他 要求名称 法律法规和其他 要求内容 运行控制 措施 检查、评价及监测结果合规性评价结果评价响应措施 1 噪声 排放中华人民共和国 建筑法 第39条：建筑施工企业有条件的应对施 工现场实行封闭管理。 封闭式管理 作业时间调 整 能严格控制强噪声作 业时间，晚间作业不超过 22时，早上作业不早于6 时。 涉及产生强噪声的成品、半 成品加工、制作作业（如钢 筋、门窗制做等），能尽量 放在工厂、车间内完成。 对强噪声机械设置了封闭 的降噪棚，以减少强噪声的 扩散。 通过对施工现场的场界噪 声检测，噪声排放值符合 BJ12523-90标准要求。 作业人员配备相应的噪声 个人防护用品的情况尤待 符合要求 封闭式管理作业时 间调整第41条：施工企业应遵守有关环保的法 律法规的规定，采取控制和处理施工现 场的各种粉尘、废气、废水、固体废物 及噪声、振动对环境的污染的措施。 中华人民共和国环 境保护法 第24条：产生环境污染和其他 公害的单位，必须把环境保护工作 纳入计划，建立环保责任制度；采 取有效措施，防治在生产活动等产 生的废气、废水、废渣、粉尘以及 噪声、振动等对环境的污染和公害 中华人民共和国环 境噪声污染防治法 第15条：产生环境噪声污染的 单位，必须保持防治环境噪声污染 的设施的正常使用。 第16条：产生环境噪声污染的
合规性评价记录表 项目名称：力创.天籁福项目部 记录编号：QB/SJS-J19-01 使用编号：安2012-001 单位，应采取措施进行治理，并按 国家规定缴纳超标排污费。 提高。 第25条：产生环境噪声污染的工业企业，应采取有效的措施，减轻噪声对周围生活环境的影响。 第29条：在市区内，建筑施工中使用机械设备，可能产生环境噪声污染的施工单位必须在开工十五日前向所在县级以上政府环保部门申报该工程的项目名称、施工场所和期限、可能产生的环境噪声值以及所采取的环境噪声污染防治措施 的情况
附件1 仿制药质量和疗效一致性评价受理审查指南 （需一致性评价品种） 一、适用范围 国产仿制药，进口仿制药。 二、资料接收/受理部门 由国家食品药品监督管理总局行政事项受理服务和投诉举报中心（简称总局受理和举报中心）接收/受理。 三、申报资料基本要求 （一）申请表的整理 1.种类与份数要求 药品补充申请表三份，一份为原件。 2.依据《关于启用新版药品注册申请表报盘程序的公告》（国家食品药品监督管理总局公告2016年第182号）要求，申请表的填报须采用国家食品药品监督管理总局统一发布的填报软件，提交由新版《药品注册申请表报盘程序》生成的电子及纸质文件。（确认所用版本为最新版〔以最新发布的公告为准〕，所生成的电子文件的格式应为RVT\MRT文件。各页的数据核对码必须一致，并须与提交的电子申请表一致，所有页码应加盖各申请人或注册代理机构骑缝章。）
3.填写应当准确、完整、规范，不得手写或涂改，并应符合填表说明的要求。 （二）申报资料的整理 1.申报资料一式三套，其中一套为原件,复印件应与原件内容保持完全一致。每套装入相应的申请表。 2.每套资料装入独立的档案袋，档案袋使用足够强度牛皮纸，以免破损。档案袋封面应注明：申请分类、药品名称、本袋所属第X套第X袋每套共X袋、原件/复印件、联系人、联系电话、手机、联系地址、邮政编码、申请人机构名称，并由申请人或注册代理机构逐袋加盖公章。 3.申报资料首页应为申报资料项目目录，目录中申报资料项目编号及项目名称均应参照《关于仿制药质量和疗效一致性评价工作有关事项的公告》（国家食品药品监督管理总局公告2017年第100号，以下简称2017年第100号公告）等有关公告通告中规定的要求提供。 4.套内各项申报资料应设独立封面，标明药品名称、资料项目编号、资料项目名称、研究单位及人员有关项目（如适用）、各申请机构名称（注册代理机构如适用）等。右上角注明资料项目编号，并由申请机构或注册代理机构逐项加盖公章。 5.资料和文件统一使用A4规格纸张。申报资料所附图片须清晰易辨，不宜使用复印图片或彩色喷墨打印方式，格式体例要求详见《药品注册申报资料的体例与整理规范》（食药监办注
合规性评价报告 （ISO14001：2015） 为了有效的控制公司的环境因素，保证环境目标的实现符合法律、法规及标准和其他要求特对公司的活动、产品和服务中适用的法律、法规和其他要求遵守情况而对公司的符合性进行评价。 评价时间：2016年05月06日。 评价地点：一楼会议室。 评价范围：公司活动、产品和服务中适用的法律、法规和其他要求。 评价人员：公司环境管理体系合规性评价小组成员。 评价依据： 1、GB/T24001：2015标准，GB/T28001:2011标准； 2、公司体系文件； 3、法律、法规和其他要求。 一、符合性的评价： 1、电能的消耗 电在我公司的运行中是不可避免需使用的资源，但在我们的控制下达到最小用电量，我们制定了《节约用电方案》对每月进行统计，对超出指标的采取改善措施。根据执行情况的检查我司是符合《中华人民共和国节约能源法》的有关规定。 2、噪声的排放
我公司在生产过程中，冲压、空压机运行过程中会产生噪声，但均不超过昼间60dB,夜间50dB（A） ,均符合《中华人民共和国环境噪声污染防治法》的有关要求，符合《工业企业厂界噪声标准》（GB12348-2008）II类区域标准。 3、污水的排放 我公司排放污水主要是洗料房、超声波清洗室、办公/清洁污水、绿化污水、汽车清洗污水.其中洗料房、超声波清洗室、水需要更换时,含油废水等其它固体废弃物没有直接排入污水管道,而是用专门容器收集,统一处理，由行政部联络有专门资质的回收公司回收；办公生活废水，生活污水经工业园生活污水排污管道排放，由污水处理厂处理，公司按要求交纳排污费用。公司也建立了《运行控制管理程序》对污水排放进行了管理。 本公司污水的排放符合《中人民共和国水污染防治法实施细则》的有关要求，符合《水污染物排放限值》（DB44/26-2001）的有关要求，符合《东莞市排污费征收管理办法》的有关要求。 4、固废的排放 a、资源的回收利用 对固体废物（废的纸箱及包装材料）的再循环利用，回收能源和资源。对危险固体废物（金属废渣、废弃的有害办公用品、生产中的带油手套等）的回收，必须根据具体的特点而定，由行政部联络有专门资质的回收公司回收,要求符合《中华人民共和国固体废弃物污染环境防治法》、本公司制定有《危化品应急预案》及《应急准备和响应程序》进行相应的控制。 B、无害化处置
仿制药一致性评价 （部分答疑） 1.原研为片剂，仿制药为胶囊，如何做一致性评价？ 答：对于该问题还在研究中。（对于这种小改剂型的没有给出明确的答复） 2.参比制剂批间批内差异过大，各点溶出差异变异系数超过相应要求怎么办？ 答：如果排除操作及设备原因，则说明该参比制剂存在问题，不适合，需重新更换参比制剂。（估计是更换欧美日被认可可做为参比制剂的仿制药） 3.如溶出曲线与参比不能完全一致，但BE一致，是否认可？答：一般情况下是可以认可的，但需要建立有区分度的溶出度方法，保证产品的质量稳定（后期所有溶出曲线必须保持与申报时一致）。 4.仿制药一致性评价时的生产验证及动态的样品是否可以销售？ 答：没有规定说不能销售。理论上只要质量合格应该是可以的。 5.参比制剂一定需要随行稳定性研究吗？溶出曲线多1条还是4条？一批还是三批？ 答：参比制剂随行稳定性研究不是必须。仅对于样品稳定性存在担忧的产品，故溶出曲线批次与溶出条件自行判断（如
对于参比批间差异小的，可以进行一批即可；溶出曲线可以仅进行具有区分度的溶出条件）。 6.参比制剂备案及审核时间太长，可否减少相关流程？ 答：目前好多品种参比制剂还不明确，需要专家仔细评估，故需要一定时间。同时也表示，如以后国家已公布了参比制剂的品种，则后期可不用备案（CFDA后期会制定我国的orange book)。 7.一致性评价目前仅针对口服固体制剂，对于其它剂型会不会要求？ 答：口服制剂占化药大半，且具有一个吸收过程；故先进行该剂型的一致性评价，后期会对其它剂型进行要求。 8.对于溶出方法开发时，有听说需要进行不同溶出仪的考察？ 答：有条件的可以在系统适用性中考察，没条件的不强制。 9.药物在某条件下不稳定，是否需与参比制剂进行比较？答：需比较；不管稳定与否，都需保持与参比制剂一致。10.对于生物等效性要求，Tmax有什么具体要求？ 答：生物等效性目前更多要求AUC、Cmax相似；对于药效与时间存在关系的，则需要关注Tmax。 11.生物等效性试验的预试验是否可以不用备案，直接进不？答：不可以； 12.对于无参比制剂的产品，是否无需药学研究，直接申请进
药品检验所对于“仿制药质量一致性评价”的思考 发表时间：2014-01-07T14:55:02.543Z 来源：《中外健康文摘》2013年第32期供稿作者：宋元德李征马晓璐王婷谭无名王淑君 [导读] 另外还有医嘱与患者病情不相符；配伍输液选择不合理；执行错误的医嘱。 宋元德李征马晓璐王婷谭无名王淑君（辽宁省辽阳市食品药品检验所 111000） 【摘要】《国家药品安全"十二五"规划》提出用5-10年时间,对2007年前批准的仿制药进行全面研究,达到仿制药与被仿制药的质量一致性, 本文通过美国、日本对“仿制药质量一致性评价”采用的措施、国内仿制药现状及药品检验所在“仿制药质量一致性评价”过程中所起的重要意义,进行了阐述。 【关键词】一致性评价溶出度仿制药 【中图分类号】R954 【文献标识码】A 【文章编号】1672-5085（2013）32-0011-02 药品是保证人民群众身体健康的特殊商品，在研发过程、生产阶段、销售环节以及使用过程的各个环节都需要进行不同程度的监管，所以，药品的质量安全至关重要。《国家药品安全"十二五"规划》明确提出要用5～10年时间，对2007年修订的《药品注册管理办法》实施前批准的基本药物和临床常用仿制药，分期分批与被仿制药进行全面比对研究，使仿制药与被仿制药的质量达到一致，对于提升制药行业整体水平，保障公众用药安全具有重要意义。本文通过美国、日本对“仿制药质量一致性评价”采用的措施、国内仿制药现状及药品检验所在“仿制药质量一致性评价”过程中所起的重要意义。 国外情况： 1998年，日本推出的“药品品质再评价工程”，其目的是为了保证口服固体药物对于不同患者都能有较高的生物利用度（BE）。使不同公司生产的不同批次的相同制剂产品均能具有相同的生物等效性。采用的方法为全面、细致、严格的四条体外溶出度试验来对药品的质量进行评估，内容为： “在严格的溶出度试验条件下，在pH1.2、4.0、6.8和水的介质中均能具有良好的溶出曲线”这一要求，来提高体内外的相关性，从而推动药品研发及生产企业对于制剂处方工艺的充分、详尽研究[1,2]。衡量制剂工艺优良与否、评价固体制剂内在品质的关键应是在低流速下、在各种pH值溶出介质中该制剂均能有一定的释放和溶出。在研发，生产以及销售过程中，利用溶出曲线严格控制药品的内在品质[3,4]。该项工程实施至今，效果明显，提高了日本的药品质量，同时，也提高了生物等效试验的成功率，降低了试验成本。2000年以后，美国的仿制药的申报数量增加，本土以外的公司，例如，以色列梯瓦、印度南新等公司，申报数量持续增长，为了客观评价仿制药品的品质[3]。美国食品药品监督局，于2004年1月推出“固体制剂溶出曲线数据库”，美国选取其中一条最能体现内在质量的曲线[3]。该溶出曲线pH值选取的出发点一般为：(1）该药物在体内消化吸收部位的pH值；(2）最能灵敏地反映制剂生产工艺变化的那条曲线；(3）溶解度最低的那条。同时该体外溶出条件可以与体内生物利用度建立体内外的相关性，且能够有效区分不同产品的质量，并具有一定的耐受性。每一个品种的溶出曲线试验方法，可随着研究的深入与时间的推移适时变更。 国内仿制药现状及药品检验所在“仿制药质量一致性评价”过程中的重要意义 我国的新药研发经过几十年的发展已经取得了巨大成就，已经改变了建国初期缺医少药情况，目前我国批准上市的药物有1.6万种，药品批准文号18.7万个，其中，化学药品0.7万种，批准文号12.1万，绝大多数为仿制药。随着医改工作的深入开展及公众生活水平的逐步提升，各界对药品质量的要求也日益提高，我国仿制药存在的一些潜在问题也越来越凸显，影响到公众用药安全[5]。在2007年以前《药品注册管理办法》修改之前，某些制药企业为了使自己的产品提前上市，缩短新药研发进程，导致部分仿制药的质量与被仿制药差距较大，一定程度上影响了仿制药的临床疗效。为提升制药行业整体水平，淘汰内在质量和临床疗效达不到要求的品种，达到或接近国际先进水平。2012年11月国家食品药品监督管理总局发布了《仿制药质量一致性评价工作方案》，利用质量一致性体外评价方法和标准，来评估药品质量。“仿制药质量一致性评价”目标是在2015年前完成口服固体制剂的一致性评价，2020年前完成注射剂及其它剂型的的一致性评价。药品生产企业是开展仿制药质量一致性评价的主体。由药品生产企业起草质量一致性体外评价方法和标准的品种，药品生产企业完成起草后，将相关资料报一致性评价办公室，由药品检验机构进行复核。“仿制药质量一致性评价”工作要求药品检验所，需完成一致性评价的相关培训，还需要完成一致性评价资料的受理、生产现场检查、抽样检验和复核等工作。同时，对于参比制剂的选择、标准的复核均需要做出相关工作。 药品检验所日常工作中，承担药品监督抽样检验和药品检验技术仲裁、药品标准拟定和药品新产品和医院制剂的技术复核工作等。平时的工作量已经十分饱满，此次“仿制药质量一致性评价”工作量大、技术含量高、时间周期短、仪器设备紧缺、经费短缺等问题；药品检验所是保证药品质量安全的技术服务部门，其在此次的“仿制药质量一致性评价”的工作中，将起到非常重要的作用。 参考文献 [1]谢沐风. 改进溶出度评价方法,提高固体药物制剂水平--论如何提高我国口服固体制剂的内在品质[J].中国药品标准,2006,7(1)43～47. [2]郭志鑫.黄志禄.姜典财.朱炯.张弛.谢沐风.中日美药品上市后质量评价体系的比较[J].中国药事,2009,23(7)718～720. [3]谢沐风.张启明.陈洁.田颂九. 国外药政部门采用溶出曲线评价口服固体制剂内在品质情况简介[J].中国药事,2008,22(3)257～261. [4]张启明.谢沐风.宁保明.庾莉菊.采用多条溶出曲线评价口服固体制剂的内在质量[J].中国医药工业杂志,2009,40(12) 946～955. [5].谢沐风. 提高质量标准,促进品质提升,带动行业发展——议如何促进国产药品的质量[J].中国医药工业杂志,2007,38(11)152～154.
作为仿制药生产大国，在我国已有批号的18.9万个药品中，仿制药占到95%以上。但由于标准低或操作不规范，多数仿制药的生物等效性与原研药有着较大差距。为提高仿制药质量，国家食品药品监督管理局于2013年初发布《关于开展仿制药质量一致性评价工作的通知》（国食药监注【2013】34号，以下简称《通知》），2015年11月18日又发布《关于开展仿制药质量和疗效一致性评价的意见（征求意见稿）》（2015年第231号，以下简称《意见》）。《意见》明确指出，2007年10月1日前批准的国家基本药物目录（2012年版）中化学药品仿制药口服固体制剂，必须在2018年底前完成一致性评价，否则将注销批准文号。其它仿制药则是自首家品种通过一致性评价后，其余相同品种在三年内仍未通过评价的，也将被注销批准文号。此次发布的《意见》具有强制性、可操作性、针对性，且有明确的时间节点要求，业内外对此高度关注。 一、开展仿制药一致性评价具有重要意义 （一）提高我国仿制药整体水平所谓仿制药，是相对原研药而言的。原研药即指原创性的新药，经过对成千上万种化合物层层筛选和严格的临床试验才得以获准上市，通常需花费15年左右的研发时间和数亿美元费用，目前只有大型跨国制药企业才有能力研制。在我国，“原研药”主要是指过了专利保护期的进口药物。仿制药则是指复制了原研药主要分子成分的药物。国产仿制药的质量与疗效与原研药存在明显差异是一个不争的事实，也是阻碍我国仿制药发展的关键因素。患者买药偏向于原研药，治疗过程中医生也倾向于推荐使用原研药。随着《意见》的正式实施，我国仿制药评价工作将实现质的飞跃。为通过一致性评价，所有仿制药生产企业将不得不提高研发和生产标准，进而提高我国仿制药行业的整体水平，实现仿制药质量和疗效与原研药在真正意义上的一致。 （二）推动医药工业创新仿制药一致性评价要求仿制药需与原研药在药学等效性（PE）、生物等效性（BE）和治疗等效性（TE）等方面达到一致，因此，以往仿制药企业那种简单的复制发展模式将不再行得通，而必须投入大量人力、物力和财力，反复进行等效性实验，进一步加强对原研药各项指标以及技术与工艺的再研究。此举对提升我国医药工业的整体创新能力具有重要意义。一方面，部分仿制药企业考虑到仿制药研发成本增加，会转移战略方向，将研发重心转向创新药。另一方面，围绕仿制药一致性评价开展的技术、工艺、疗效等方面的再研究，也有助于提升企业的消化吸收和再创新能力。 （三）提高行业集中度目前，我国医药产业存在多、小、散、乱的现象，仿制药企业数量占到了全部药品生产企业的90%以上。新政颁布实施后，一些中小企业很可能会因为通过一次性评价成本较高而放弃文号甚至放弃生产，进而出现中小企业关闭或被大企业兼并的局面。可见，新政的实施有利于淘汰落后产能，提高行业集中度，完善企业组织结构。（四）推动仿制药走向国际市场我国仿制药市场主要集中在国内，质量不高成为出口的制约性因素，通过世界卫生组织PQ认证、美国cGMP认证、欧盟GMP认证、澳大利亚TGA认证和英国MHRA认证等国际认证的企业目前还较少。例如，在2009年的WHO采购目录中，我国进入目录的品种是6个，而另一仿制药大国印度进入目录的品种则多达194个。通过强制性开展仿制药一致性评价，有助于提高我国仿制药的整体质量与疗效水平，提升国际竞争力，推动国产仿制药的出口。 二、新政实施需关注的三个问题 （一）仿制药格局调整将带来药品供给变化一是大量文号将消失。在仿制药一致性评价新政中，明确要求2007年10月1日前批准的国家基本药物目录（2012年版）中化学药品仿制药口服固体制剂，应在2018年底前完成一致性评价，否则将注销药品批准文号。实际上，我国95%的仿制药上市许可证都是2007年之前批准的，而且，口服固体制剂包括药片、胶囊、颗粒、滴丸、膜剂等剂型，占到了所有化学仿制药的70%以上。这些因素客观上决定了几乎大部分仿制药都要在2018年底前完成一致性评价，否则会被注销文号。企业要通
刚刚！！CFDI发布仿制药一致性评价现场检查-企业指南 为规范仿制药一致性评价现场检查工作，持续提高检查工作质量和效率，在原国家食品药品监督管理总局仿制药质量和疗效一致性评价相关文件的框架下，核查中心组织起草了《企业指南：质量和疗效一致性评价仿制药品药学研制现场检查要求》和《企业指南：质量和疗效一致性评价仿制药品生产现场检查要求》，现向社会公开征求意见。请于2018年5月3日前将有关意见或建议以电子邮件形式反馈至核查中心。真诚感谢一直以来对我中心工作的支持。 原国家食品药品监督管理总局食品药品审核查验中心（暂）2018年4月2日 企业指南：质量和疗效一致性评价仿制药品药学研制现场检查要求（草案） 一、前言 为保证开展质量和疗效一致性评价的仿制药品药学研制现场检查工作的质量和效率，特制定本要求，本指南仅代表食品药品审核查验中心目前对相关事宜的考虑，将根据CFDA 对检查工作的政策要求适时进行调整。 本指南所提及的仿制药具体指：化学药品新注册分类实施前批准上市的需开展一致性评价的仿制药。 本指南所指的检查要求主要包括：申请人在接受现场检查
时，需提前准备的与产品注册、研制现场相关的资料和人员要求。 二、资料要求 （一）首次会议企业汇报资料 首次会议需要生产企业以幻灯片的形式介绍如下内容： 药品研制基本情况（如属委托，应说明被委托研究单位基本情况）。 研制所涉及的批次（含BE批）批量用途，研制批次（含BE 批）生产的地址、生产线、时间地点、使用量和剩余量等。研制批次（含BE批）所用处方生产工艺、原辅料包装材料来源及标准、生产线（设备设施）、产品质量标准（含中间控制标准）等是否与已上市/拟上市商业化生产规模的批次一致。 参比制剂的来源、采购和使用情况。 药品和参比制剂体外研究的对比研究情况，研究时间、批号和研究结果 药品关键质量属性（含稳定性）研究情况。 （二）检查时需事先准备的文件（尽可能提供原始文件）接受现场检查品种仿制药质量和疗效一致性评价全套注册申报资料。 委托研究协议和质量协议，如有。 参比制剂的来源及证明，如购买发票、赠送证明等。参比制
仿制药质量和疗效一致性评价百问百答 （第2期） 仿制药质量与疗效一致性评价办公室 2018年4月7日
目录 参比制剂相关问题 ................................................................................. 错误！未定义书签。 1、问：《已发布参比制剂有关事宜的说明》中（仅限欧美日企业）是对总公司限定 还是对持证商限定？............................................................... 错误！未定义书签。 2、问：在已公布的参比制剂在指定的上市国（仅限欧美日企业）说明书中存在多个 生产商的，如何确定参比制剂？............................................. 错误！未定义书签。 3、问：缓控释制剂的参比制剂如何选择？ ................................. 错误！未定义书签。 4、问：为何暂停销售状态的原研进口药品依然被推荐为参比制剂？错误！未定义书 签。 5、问：原研未进口，但在国外多个国家上市，在参比制剂遴选时的考虑因素有哪 些？ ........................................................................................ 错误！未定义书签。标识使用相关问题 . (3) 1、问：“通过一致性评价”标识的图样、颜色、字体是否可以进行自行调整？ (3) 2、问：“通过一致性评价”标识下方的公告号如何印制？ (3) 一致性评价生物等效性试验备案平台相关问题 (4) 1、问：仿制药一致性评价的BE试验/临床有效性试验备案平台（以及新报仿制药BE 试验备案平台），在备案先后开展的同一药物的不同试验时，如何备案？ (4)
一致性评价最新进展 一致性评价全称仿制药质量和疗效一致性评价，其要求已经批准上市的仿制药品要在质量和疗效上与原研药品能够一致，临床上与原研药品可以相互替代。美国、日本、欧洲等医药发达地区均已经开展仿制药一致性评价工作，我国也于2012年启动一致性评价工作。 一、我国一致性评价进程 1、第一次启动，无实质进展 我国第一次启动仿制药一致性评价始于2012年1月20日，国务院发布《国家药品安全“十二五”规划》（国发[2012]5号）提出全面提高仿制药质量,分期分批开展仿制药一致性评价，提出“国家基本药物目录、临床常用的仿制药在2015年前完成”，但直到2014年底，一致性评价工作基本陷入停滞状态。 2、第二次启动，迅猛推进 2015年8月18日，国务院发布《关于改革药品医疗器械审评审批制度的意见》（国发[2015]44号），明确指出加快仿制药质量一致性评价，力争2018年底前完成国家基本药物口服制剂与参比制剂质量一致性评价，一致性评价第二次启动，并高效迅猛执行，仅2个月内就发布了《参比制剂选择和确定》、《人体生物等效性研究技术》、《溶出曲线测定与比较》等核心技术方案的征求意见稿。2016年3月5日，国务院办公厅印发《关于开展仿制药质量和疗效一致性评价的意见》（国办发[2016]8号），要求2007年10月1日前批准上市的化学药品仿制药口服固体制剂（即289目录），应在2018年底前完成
一致性评价，随着此文件发布，进入政策推动密集期。 一致性评价工作相关政策 二、开展一致性评价的意义 1、有利于提高药品的有效性。通过一致性评价工作，我国仿制药质量能够得到大幅提升，百姓用药的有效性也能随之得到保障。 2、有利于降低百姓用药支出，节约医疗费用。通过一致性评价的仿制药，其质量跟原研药一样。临床上优先使用这些“可替代”的仿制药，能够大大降低百姓的用药负担，减少医保支出，提高医保基金的使用效率。 3、有利于提升医药行业发展质量，进一步推动医药产业国际化。仿制药一致性评价，将持续提高我国的药用辅料、包材以及仿制药质量，加快我国医药产业的优胜劣汰、转型升级步伐，提升我国制剂生产水平，进一步推动我国制剂产品走向国际市场，提高国际竞争能力。 4、有利于推进供给侧结构性改革，优化产业布局。一致性评价
附件3 仿制药质量一致性评价人体生物等效性研究 技术指导原则 一、概述 药物制剂要产生最佳疗效，其药物活性成分应当在预期时间段内释放吸收并被转运到作用部位达到预期的有效浓度。大多数药物是进入血液循环后产生全身治疗效果的，作用部位的药物浓度和血液中药物浓度存在一定的比例关系，因此可以通过测定血液循环中的药物浓度来获得反映药物体内吸收程度和速度的主要药代动力学参数，间接预测药物制剂的临床治疗效果，以评价制剂的质量。允许这种预测的前提是制剂中活性成分进入体内的行为是一致并且可重现的。 生物利用度（Bioavailability,BA）是反映药物活性成分吸收进入体内的程度和速度的指标。过去出现的一些由于制剂生物利用度不同而导致的不良事件，使人们认识到确有必要对制剂中活性成分生物利用度的一致性或可重现性进行验证，尤其是在含有相同活性成分的仿制产品要替代它的原研制剂进入临床使用的时候。鉴于药物浓度和治疗效果相关，假设在同一受试者，相同的血药浓度-时间曲线意味着在作用部位能达到相同的药物浓度，并产生相同的疗效，那么就可以药代动力学参数作为替代的终点指标来建立等效性，即生物等效性（Bioequivalence, BE）。
BA和BE研究已经成为评价制剂质量的重要手段。本指导原则将重点阐述BA和BE研究的相关概念、应用范围和BA和BE研究的设计、操作和评价等。 本指导原则主要是针对化学药品普通固体口服制剂质量一致性评价的人体生物等效性研究。因为在具体应用过程中有可能面临多种情况，对于一些特殊问题，仍应遵循具体问题具体分析的原则。 二、BA和BE基本概念及应用 1.生物利用度：是指药物活性成分从制剂释放吸收进入全身循环的程度和速度。一般分为绝对生物利用度和相对生物利用度。绝对生物利用度是以静脉制剂（通常认为静脉制剂生物利用度为100%）为参比制剂获得的药物活性成分吸收进入体内循环的相对量；相对生物利用度则是以其他非静脉途径给药的制剂（如片剂和口服溶液）为参比制剂获得的药物活性成分吸收进入体循环的相对量。 2.生物等效性：是指药学等效制剂或可替换药物在相同试验条件下，服用相同剂量，其活性成分吸收程度和速度的差异无统计学意义。通常意义的BE研究是指用BA研究方法，以药代动力学参数为终点指标，根据预先确定的等效标准和限度进行的比较研究。在药代动力学方法确实不可行时, 也可以考虑以临床综合疗效、药效学指标或体外试验指标等进行比较性研究，但需充分证实所采用的方法具有科学性和可行性。 了解以下几个概念将有助于理解BA和BE： 原研药（Innovator Product）：是指已经过全面的药学、药
仿制药一致性评价及其评价过程的质量管理 发表时间：2020-01-10T16:39:12.860Z 来源：《医药前沿》2019年35期作者：王晓龙吴爽胡瑾[导读] 本文首先介绍了仿制药一致性评价研究的特点，并结合我国目前存在的问题，探讨提升我国仿制药质量水平的举措。 （杭州中美华东制药江东有限公司浙江杭州 310000） 【摘要】提升仿制药质量的一个关键步骤是仿制药一致性评价，其评价质量的高低直接关系到医药产业能否顺利升级、国家供给侧改革能否顺利完成以及公众健康福利有无保障。为此，相关部门必须重视加强仿制药一致性评价的质量管理工作，提高仿制药一致性评价的研究和工作效率。本文首先介绍了仿制药一致性评价研究的特点，并结合我国目前存在的问题，探讨提升我国仿制药质量水平的举措。 【关键词】一致性评价；质量管理；仿制药；指纹图谱化 【中图分类号】R965.3 【文献标识码】A 【文章编号】2095-1752（2019）35-0250-01 1.我国仿制药研制现状 我国仿制药行业飞速发展，然而仿制药与原研药在质量和疗效上的差异不容忽视，如二甲双胍制剂，在抽检过程中发现一些仿制品体外溶出度与原研药相差较多；在临床实践过程中，存在仿制药与原研药疗效上的差异，甚至同一企业不同批次之间也存在疗效差异。这些差异的产生，与我国仿制药技术水平、药品申报审批过程中存在的技术缺陷相关。中国本土企业生产的药品中，仿制药占比97%。以固体口服剂为例，有298种在产，国家批准文号已超20000个，包括600多种不同规格，药品生产线涉及上千家生产企业。然而，由于各企业在制药原材料、制药人员以及工艺流程等方面均存在较大差异，使得生产出来的仿制药品与原研药之间存在较大差异。 2.仿制药一致性评价研究的特点 仿制药生产企业需要以原研药作为对照，为达到与原研药相近的药效，全面深入地开展比对研究，主要包括以下两个方面：一方面，比较仿制药与原研药的药学效果，可以从处方、质量标准、晶型、粒度和杂质、溶出曲线等主要药学指标比较研究；另一方面，比较仿制药与原研药的生物效果，可以从通过临床生物等效试验证明体内生物利用度一致，最终实现用药治疗等效。从研究内容方面看，仿制药一致性评价过程近似于仿制药的研发，因此，也具有仿制药研发项目所具有的创新性优点以及不确定性和潜在的危险性等缺点。同时，受国家仿制药相关的政策法规的要求，仿制药一致性评价研究具有强制性和时限性[1]。 3.一致性评价研究存在的主要问题 目前，我国仿制药一致性评价研究中主要存在以下几个问题：第一，仿制药的研发不规范，尚未形成明确的质量标准，国家尚未出台仿制药药品研发控制的法律文件，此外，缺乏仿制药药品质量的核查机制；第二，仿制药研发实验的流程设计存在问题，如药品研究方案不具体，很多科研人员进行大量无意义的反复实验，记录无价值的实验笔记，浪费人力、物力和财力；第三，仿制药研发实验数据可能不可靠，实验人员记录的报告不完整，导致药品实验结果不正确，参考价值不大，一旦出错，难以追溯原因；第四，药品研发的质量和进度难以平衡，在实际生产和应用的过程中，往往会重视药品质量而忽视研发进度，或者过于注重研发进度而忽视药品质量，导致仿制药质量审查时出现很多质量问题。生产过程作为制药流水线的第一步，直接决定了药品质量的好坏。为了提高仿制药品的质量，对于药品生产企业而言，首先应当严格要求自己，按照国家《药品生产质量管理规范》的相关规定，控制制药过程的每一步，杜绝后续药检的不合格现象；其次，加强工作人员队伍建设，提高队伍专业素质，企业上下都应将药品的质量放在首位，以保证广大人民群众的用药安全[2]。 4.一致性评价研究质量管理改进建议 4.1 质量一致性应以GMP为基础 GMP标准，指的是药品生产质量管理规范，是国家相关部门为了保证药品的质量而专门制定的，旨在最大程度地降低药品生产过程中的不合格风险。药品质量的一致性评价都应以GMP作为基础，对于仿制药产品的生产而言，应当满足以下几个方面：第一，所有药品的研制都应满足国际GMP的质量标准和要求，切不可违规生产；第二，注重仿制药与原研药的药学效果和生物效果的一致性，确保仿制药药品本身不存在质量问题，影响药品疗效[3]；第四，仿制药应当与原研药具有相同的安全性，一切药品的生产都应当以病患的健康为大前提；第五，药品都应当配备准确的说明书，方便地指导病患安全用药。此即仿制药与原研药的“五层一致性要素”，是国际上公认的仿制药一致性要素。同时，某些发达国家对药品的生产有更为具体的要求，即药品的研究试验、生物等效性试验都尽量在大生产模拟条件下进行。因此，在仿制药的研发过程种，首先要保证药品生产条件的安全性，符合国家和行业内部的研发要求。其次，基础的药学研究需要保证处方、成分含量及药效稳定性与原研药品一致，进而可以考虑大批量地投入临床研究，最终做到仿制药与原研药的生物效果一致。最后，给予病患详细的用药说明书，概述研发阶段所得到的可靠结论。由于质量具有累积效应，高层级的质量是在满足初始层级质量要求下实现的。当初始层级要求未达到时，高层级的一致性便无从谈起。我国的GMP起步较晚，质量监管理念有待提高。 4.2 将一致性评价纳入全面质量管理的标准化体系 使用指纹图谱化技术全面提高仿制药的质量。指纹图谱是指能够标示其化学特征的谱图，基本原理是利用仿制药的主要成分，经适当处理，采用指纹图谱的分析手段，揭示药品特征。指纹图谱化技术具有系统性、稳定性以及可靠性等优点，获得了较为广泛的应用。从仿制药开发研究、生产到销售的每一步，都应将质量管理指纹化、标准化，形成具有较高参考价值的实验记录，加强对仿制药质量可靠性程度的有效控制，以更好地保证仿制药与原研药的疗效一致，提高实验成功率，同时还能节省制药企业的投资成本。 5.结语 仿制药一致性评价工作如果无法有效进行，就无法及时筛查出疗效不达标的仿制药，从而影响患者用药安全，危害身体健康，还会阻碍我国仿制药生产企业的发展和进步。因此，为提高仿制药一致性评价的质量管理效率，必须严格控制制药过程的每一步，严格执行开发过程中的管理规范，增强过程质量管理控制，加强企业内部自检及国家监督管理，实现一致性评价质量管理全面提升。 【参考文献】 [1]丁锦希，刘莹芳，郑翠微等.我国仿制药一致性评价品种探析[J].上海医药,2017，7(8):54-57. [2]陈红英.仿制药一致性评价研究的质量管理[J].中国临床药理学杂志,2018,34(8):993-995.
推进仿制药一致性评价提升行业发展水平 ——仿制药质量和疗效一致性评价有关政策解读 2015年8月，国务院启动药品医疗器械审评审批制度改革，其中推进仿制药质量和疗效一致性评价（以下简称“仿制药一致性评价”）是改革的重点任务之一。今年3月5日，国务院办公厅印发的《关于开展仿制药质量和疗效一致性评价的意见》（国办发〔2016〕8号）（以下简称《意见》）正式对外公布，标志着我国已上市仿制药质量和疗效一致性评价工作全面展开。随后，国家食品药品监管总局出台《关于发布仿制药质量和疗效一致性评价参比制剂备案与推荐程序的公告》（2016年第99号）、《关于发布仿制药质量和疗效一致性评价工作程序的公告》（2016年第105号）等一系列文件。5月26日，总局又发布了《关于落实〈国务院办公厅关于开展仿制药质量和疗效一致性评价的意见〉的公告》（2016年第106号），（以下简称《公告》）对仿制药一致性评价工作进行了部署。6月21-22日，总局在北京召开了仿制药质量和疗效一致性评价的工作会议，贯彻落实国务院关于仿制药质量和疗效一致性评价的意见，深入推进药品审评审批制度改革。 开展仿制药一致性评价，是《国家药品安全“十二五”规划》提出的重要任务，是国家食品药品监督管理总局自成立以来为保证群众用药安全有效所采取的一项重大举措，将对医药产业健康发展产生深远影响。也因为此，仿制药一致性评价也是近一段时期以来医药行业内关注度较高的问题。现就一致性评价有关政策问题进行解读。 一、为什么要开展仿制药一致性评价？ 对已经批准上市的仿制药进行一致性评价，这是补历史的课。因为过去我们批准上市的药品没有与原研药一致性评价的强制性要求，所以有些药品在疗效上与原研药存在一些差距。历史上，美国、日本等国家也都经历了同样的过程，日本用了十几年的时间推进仿制药一致性评价工作。开展仿制药一致性评价，可以使仿制药在质量和疗效上与原研药一致，在临床上可替代原研药，这不仅可以节约医疗费用，同时也可提升我国的仿制药质量和制药行业的整体发展水平，保证公众
. 附件3 仿制药质量一致性评价人体生物等效性研究 技术指导原则 一、概述 药物制剂要产生最佳疗效，其药物活性成分应当在预期时间段内释放吸收并被转运到作用部位达到预期的有效浓度。大多数药物是进入血液循环后产生全身治疗效果的，作用部位的药物浓度和血液中药物浓度存在一定的比例关系，因此可以通过测定血液循环中的药物浓度来获得反映药物体内吸收程度和速度的主要药代动力学参数，间接预测药物制剂的临床治疗效果，以评价制剂的质量。允许这种预测的前提是制剂中活性成分进入体内的行为是一致并且可重现的。 生物利用度（Bioavailability,BA）是反映药物活性成分吸收进入体内的程度和速度的指标。过去出现的一些由于制剂生物利用度不同而导致的不良事件，使人们认识到确有必要对制剂中活性成分生物利用度的一致性或可重现性进行验证，尤其是在含有相同活性成分的仿制产品要替代它的原研制剂进入临床使用的时候。鉴于药物浓度和治疗效果相关，假设在同一受试者，相同的血药浓度-时间曲线意味着在作用部位能达到相同的药物浓度，并产生相同的疗效，那么就可以药代动力学参数作为替代的终点指标来建立等效性，即生物等效性（Bioequivalence, BE）。
BA和BE研究已经成为评价制剂质量的重要手段。本指导原则将重点阐述BA和BE研究的相关概念、应用范围和BA和BE研究的设计、操作和评价等。 本指导原则主要是针对化学药品普通固体口服制剂质量一致性评价的人体生物等效性研究。因为在具体应用过程中有可能面临多种情况，对于一些特殊问题，仍应遵循具体问题具体分析的原则。 二、BA和BE基本概念及应用 1.生物利用度：是指药物活性成分从制剂释放吸收进入全身循环的程度和速度。一般分为绝对生物利用度和相对生物利用度。绝对生物利用度是以静脉制剂（通常认为静脉制剂生物利用度为100%）为参比制剂获得的药物活性成分吸收进入体内循环的相对量；相对生物利用度则是以其他非静脉途径给药的制剂（如片剂和口服溶液）为参比制剂获得的药物活性成分吸收进入体循环的相对量。 2.生物等效性：是指药学等效制剂或可替换药物在相同试验条件下，服用相同剂量，其活性成分吸收程度和速度的差异无统计学意义。通常意义的BE研究是指用BA研究方法，以药代动力学参数为终点指标，根据预先确定的等效标准和限度进行的比较研究。在药代动力学方法确实不可行时, 也可以考虑以临床综合疗效、药效学指标或体外试验指标等进行比较性研究，但需充分证实所采用的方法具有科学性和可行性。 了解以下几个概念将有助于理解 BA和BE： 原研药（Innovator Product）：是指已经过全面的药学、—16—