A Survey of Postapproval CMC Changes to Generic Drugs

Upon regulatory approval of a new drug product, an applicant may propose postapproval changes to the product for various reasons, such as continuous improvement, compliance with compendial standards, and new suppliers or manufacturers for different components of the drug product.  To do so, an applicant must notify FDA about each postapproval change via supplement or annual report, and also assess its effects before distributing a drug product made with such a change (1). The majority of the post-approval changes received by FDA are chemistry, manufacturing, and control (CMC) changes that may affect the following aspects of drug substances and/or drug products: components and composition, manufacturing sites, manufacturing process, specifications, container closure system, labeling, and multiple related changes (2, 3). An applicant needs to submit a postapproval change request in the form of a supplemental (abbreviated) new drug application (sNDA/sANDA, or supplement), or needs to describe the changes in an annual report. These post-approval CMC changes may directly or indirectly affect the drug product quality and safety, and thus need to be evaluated by FDA using a risk- and science-based approach.

Based on the potential risk to product identity, strength, quality, purity or potency, postapproval CMC changes can be divided into four reporting categories (2):

• Prior Approval Supplement (PAS)—to report major changes that have substantial potential to adversely affect the drug product.  Major changes need regulatory approval prior to distributing the drug product made using the proposed changes.

• Supplement Changes Being Effected in 30 Days (CBE 30)—to report moderate changes that have moderate potential to adversely affect the drug product at least 30 days prior to distributing the drug product made using the proposed changes. If FDA informs the applicant about missing information within 30 days of receiving a CBE 30, product distribution must be delayed until the CBE 30 is satisfactorily amended.  

• Supplement-Changes Being Effected (CBE 0)—to report certain moderate changes for which product distribution can occur when FDA receives the supplement. If found not approvable upon regulatory review, FDA may order the applicant to cease the distribution of the drug product made using the proposed changes.

• Annual Report—to report minor changes that have minimal potential to adversely affect the drug product.  An applicant must describe minor changes in its next annual report.

Sufficient supporting information needs to be submitted to FDA to justify the proposed changes.  Different review timelines and strategies are used for different reporting categories.

Generic drugs play an increasing role in the US-healthcare system, saving billions of dollars each year while providing equivalent therapeutic effects just as their brand name counterpart.  For instance, nearly 80% of prescriptions were filled with generic drug products in 2011 with a projection of 87% in 2015.  The cost savings of the generic program alone for 2011 was $192.8 billion (4, 5). All stakeholders, therefore, are allocating more attention and resources to generic drugs, while paying particular attention to their overall quality and safety.  As part of product lifecycle management, appropriate postapproval CMC changes are crucial for quality assurance and continuous improvement.

Herein results are provided from a recent data-mining survey focused on postapproval CMC changes to approved generic-drug products. The goal is to reemphasize the criticality of postapproval product quality management, to improve the supplement submission quality from applicants, and to share the concept that the approval of a generic-drug product is just the beginning of its lifecycle.

METHODS
Postapproval CMC changes submitted to the Office of Generic Drugs (OGD) between calendar years 2005 and 2012 were surveyed from FDA’s internal database. Qualitative and quantitative analyses were conducted upon categorizing these changes based on their nature, risk, and regulatory designations. Here we define “nature” as what is proposed to be changed, “risk” as potential adverse impact of the proposed changes on product quality and safety, and “regulatory designations” as filing categories identified by FDA after regulatory review.  In addition, review outcomes (e.g., commonly seen deficiencies, comments, and filing issues) from OGD were summarized to identify major issues and areas.

In this article, the two terms “supplement” and “postapproval change” are not inter-changeable because a supplement may contain or propose more than one postapproval change.  Considering such a fundamental difference, the number of supplements and number of postapproval changes discussed in this article are different.

RESULTS AND DISCUSSIONS
On average, OGD received more than 3500 supplements each year within the survey period, and the yearly number of supplements submitted to OGD stayed relatively constant. Figure 1 shows a distribution summary for these supplements based on reporting categories designated by FDA upon review. As shown, the number of CBEs and CBE 30s received per year remained similar at ~20% and ~65%, respectively.  However, the number of high-risk changes (i.e., PAS) appeared to be on the rise and they currently constitute approximately 10% of all the incoming supplements.  

There is a discrepancy between the numbers/percentages of supplements submitted by applicants and FDA in regard to reporting categories. This is mainly due to the difference in risk assessment for certain changes between applicants and FDA. As a result, FDA evaluated some supplements to reflect an apparently higher risk with a given change.  Reporting category elevation statistics are summarized in Table I.  Also, some supplements were downgraded upon review, such as CBE 30 downgraded to CBE or annual report.  The proper filing category designation is crucial especially after implementing the Generic Drug User Fee Amendments of 2012 (GDUFA).  As prescribed by the GDUFA legislation, a proper amount of fee (e.g., $25,760 for fiscal year 2013, and $31,930 for fiscal year 2014) needs to be paid to FDA upon submitting a PAS (major changes) (6), while no fee is required for submitting CBE 30, CBE, and annual reports.  In addition, different review timelines are assigned to different reporting categories.  In other words, proper supplement filing may significantly save resources and improve regulatory efficiency for both the applicant and FDA

Table I. Summary of the elevation of applicant claimed moderate risk changes to high risk reporting categories upon FDA’s risk assessment.

Calendar Year

CBE elevated to PAS

CBE 30 elevated to PAS

2005

25

30

2006

8

62

2007

77

279

2008

19

132

2009

3

109

2010

12

118

2011

18

134

2012

24

126

Applicants and FDA, therefore, need to conduct rigorous risk assessment for each proposed CMC change to determine and safeguard the proper filing category of a supplement, and to ensure that a supplement is processed accordingly. It should be noted that within a given supplement with multiple changes, one high-risk change automatically elevates the entire supplement into a high-risk reporting category, which is independent of the number of low-risk changes accompanying the high-risk change.

Figure 2 summarizes commonly seen CMC changes, using data from calendar year 2012 to show a typical distribution of these changes.  It is noticeable that three cohorts (i.e., facility, control, and manufacturing process) constitute nearly 85% of the proposed CMC changes in calendar year 2012. Table II provides further clarifications for these cohorts. Typically, postapproval changes in these cohorts are costly for applicants and resource consuming for both applicants and FDA, and may even delay product commercialization or lead to product recalls.  

To better manage such a high volume of postapproval CMC changes for generic drugs, FDA established a dedicated review team, the Supplement Review Team (SRT), in May 2012.  The objectives of the SRT include: to increase the consistency and efficiency reviewing postapproval CMC changes; to enhance the collaboration among multiple disciplines within FDA; and to improve communication between FDA and applicants to foster a risk- and science-based regulatory environment. Following a risk- and science-based approach, SRT reviews postapproval changes in two steps. The first step is to conduct risk assessment of proposed CMC changes to designate an appropriate reporting category for the overall supplement; the second step is to conduct an in-depth scientific review of the supplement. As mentioned previously, the first step may result in different reporting category designations of a supplement between applicants and FDA.

Table II. Further descriptions about three main cohorts of postapproval chemistry, manufacturing and controls (CMC) changes, reported to FDA in calendar year 2012.

CMC Changes

Description

Facility (34.3%)

This cohort introduces new facility(ies) to marketed generic drug products.  New facilities may include testing facility, packaging site, manufacturing site for drug substance and/or drug product, and inactive ingredient source.

Control (33.5%)

This cohort introduces changes to controls of drug substance and/or drug product, such as specifications, in-process control, and stability protocol.

Manufacturing Process (15.9%)

This cohort introduces changes to manufacturing process of drug substance and/or drug product, such as scale up/down, equipment change, alternative manufacturing process, and new synthetic route for drug substance.

As observed above, applicants have reported more major changes (i.e., PASs) in recent years.  On one hand, some major changes are being introduced to marketed generic-drug products due to various intended reasons, such as continuous improvements, adoption of new equipment and technologies, and reducing in-process control thanks to enhanced process understanding. On the other hand, some major changes are proposed due to various unintended reasons, such as out-of-specification (OOS) results, inability to scale up an approved manufacturing process, and new drug substance source due to a broken supply chain.  Although applicants may not have control over some unintended situations (e.g., supply chain issues), improved process understanding and proper lifecycle management of generic drugs may reduce the number of high-risk changes.  For instance, some costly CMC changes can be avoided or eliminated by better understanding the drug product and/or manufacturing process especially in the premarket phase, and by using proper quality metrics (7) to adequately monitor and control product manufacturing and quality in the lifecycle management.      

COMMON ISSUES
This section briefly summarizes commonly seen issues observed during this survey and a daily review of postapproval CMC changes, and accordingly, FDA’s expectations on how to improve supplement submission quality.  Commonly seen issues include:  
• Section(s) of the 2004 guidance (2) not cited to justify reporting category
• Lack of risk assessment to determine proper reporting category
• Lack of scientific reasons and/or rationale to support proposed changes
• Lack of proper investigation for OOS results
• Use of OOS results to justify new specification
• Reliance on data to justify reporting category
• Introduction of future CMC changes without supporting information
• Additional changes not listed in the cover letter
• No inspection date for site changes
• Lack of conciseness/clarification
• Too much unnecessary information provided.

To improve submission quality and facilitate timely review of thousands of CMC changes yearly, it is recommended that applicants do the following:
• Properly assess risks of proposed changes against published guidance (2, 3, 8-12), quality-by-design (QbD) principles, and/or internal knowledge
• Choose reporting category based solely on the risk assessment
• Clearly identify all proposed changes with brief risk assessment in the cover letter
• Provide supporting information necessary and sufficient to justify proposed changes.

CONCLUSION
FDA receives more than 3500 supplements to marketed generic drugs each year.  Proposed postapproval CMC changes directly impact product quality and performance, and eventually patient safety.  Given the increasing importance of generic drugs in the US pharmaceutical supply chain, FDA is allocating more resources to ensure the timely evaluation of these postapproval changes.  It is also applicants’ responsibility to improve submission quality according to risk- and science-based principles, and to enhance lifecycle management of generic drugs using proper quality metrics (e.g., process capability). The authors believe that the findings presented here can provide valuable reference for the generic industry to submit high quality supplements, and for FDA to more efficiently manage and review them.

REFERENCES
1. Code of Federal Regulations, Title 21, Food and Drug, Part 314.70 (Government Printing Office, Washington, DC).
2. FDA, Guidance for Industry Changes to an Approved NDA or ANDA (Rockville, MD, Apr.  2004).
3. FDA, Guidance for Industry Changes to an Approved NDA or ANDA Questions and Answers (Rockville, MD, January 2001).
4. FDA, Facts About Generic Drugs (September 2012).
5. Generic Pharmaceutical Association, Generic Drugs Saving in the US (Fourth Annual Edition: 2012).
6. FDA, “Generic Drug User Fee-Abbreviated New Drug Application, Prior Approval Supplement, Drug Master File, Final Dosage Form Facility, and Active Pharmaceutical Ingredient Facility Fee Rates for Fiscal Year 2014,” Federal Register 78(149): 46977-46981(2013).
7. Barlas, S., Pharm. Techn. 38(5): 261-263 (2013).
8. FDA, Guidance for Industry CMC Postapproval Manufacturing Changes Reportable in Annual Reports (Silver Spring, MD, June 2010).
9. FDA, Guidance for Industry PAC-ATLS: Postapproval Changes: Analytical Testing Laboratory Sites (Rockville, MD, Apr. 1998).
10. FDA, Guidance for Industry Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls: In Vitro Release Testing and In Vivo Bioequivalence Documentation (Rockville, MD, May 1997).
11. FDA, Guidance for Industry SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (Rockville, MD, Sep. 1997).
12. FDA, Guidance for Industry Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (Rockville, MD, Nov. 1995).

Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

About the Author
Geoffrey Wu, PhD, is a regulatory review officer, [email protected], Lane Christensen, PhD, is a chemist, Andrew Tran is a senior health service officer, David Holovac is a pharmacist, Benjamin Danso, Pharm.D., is regulatory project manager, Larisa Wu, PhD, is a chemist, and Paul Schwartz, PhD, is a supervisory chemist, Andrew Zhang, intern, all at FDA, CDER’s Office of Generic Drugs. Zhaoxin Yang is a student at University of Maryland, School of Medicine, Baltimore, Maryland, and Lawrence Yu, PhD, is the acting director at FDA, CDER’s Office of Pharmaceutical Science.