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This article provides a PhRMA perspective and recommendations on an FDA guidance currently under development dealing with postapproval changes after the final intermediate of the active pharmaceutical ingredient, i.e., BACPAC II. The concept of a "last true solution" is proposed as an additional point in the assessment of potential risk associated with process changes.
The US Food and Drug Administration has issued a Guidance for Industry entitled BACPAC I: Intermediates in Drug Substance Synthesis (1) but has yet to issue a companion document that would cover postapproval changes from the final intermediate to the active pharmaceutical ingredient (API). Because of the significant value in a guidance that will provide clarification as well as regulatory relief for late-stage API postapproval changes, the Pharmaceutical Research and Manufacturers of America's (PhRMA's) API Technical Group assembled a working group to compile industry recommendations for consideration by FDA in the development of BACPAC II, as it had done for BACPAC I (2).
The US regulatory environment for chemistry, manufacturing, and control (CMC) issues is changing rapidly, driven largely by FDA's new Pharmaceutical Quality for the Twenty-First Century initiative. Under this system, changes to API processes will be assessed on the basis of risk with regards to concepts of quality-by-design (e.g., design space, critical process parameters, process analytical technology [PAT]) that are used to develop robust API manufacturing processes. Accordingly, it is understood that a future FDA guidance addressing both API documentation for original new drug applications and postapproval changes might be appropriate under the new system. For some period of time, however, there will be many legacy products on the market for which more traditional development principles were followed. For such products, the present discussion would be applicable in terms of defining potential areas for regulatory clarification and relief.
The PhRMA BACPAC II Working Group identified the following important concepts, which industry hopes FDA will consider during the development of the new BACPAC II guidance:
To show how these concepts can be applied, the PhRMA Working Group has developed a proposed BACPAC II decision tree and has worked with a specifications and BACPAC Working Group operating under the direction of the Product Quality Research Institute (PQRI). The PQRI group also has developed a BACPAC II proposal that is fundamentally aligned with this position paper.
PhRMA believes that this decision tree represents an approach that will provide clarification and regulatory relief for industry while respecting the concept that the later in the process that a change occurs, the more significant the potential for adverse impact. Nonetheless, it is also reasonable to believe that the proposals contained herein representing late-stage regulatory relief can be achieved without compromising quality or public safety, particularly because all changes will require data to demonstrate that there is no adverse effect.
The PhRMA Working Group recommendations focus on the determination of the filing category. It is fully recognized that ultimately BACPAC II, as in BACPAC I, also will contain guidance for supporting data to be included in the regulatory submissions. Although the latter is not discussed in detail in this article, the group requests that FDA also consider the nature and potential influence of the change in determining its recommendations for supporting data.
In general, PhRMA believes that, other than in cases of changes with high potential risk (e.g., prior-approval changes), drug product data should not be required in support of the regulatory filing for API changes. Acceptance of this point lies in the concept that all relevant API (or any post–final intermediate) quality standards be identified and included in pre- and postchange quality comparisons. As we discuss, such relevant quality standards may extend beyond regulatory specifications and must be carefully assessed on a case-by-case basis.
In the late 1990s, FDA began to draft a guidance document to cover postapproval changes to API manufacturing. In response to that initiative, a PhRMA BACPAC Working Group published its recommendations for FDA consideration in its development of a single guidance document for bulk active postapproval changes (BACPAC) (2). These recommendations included an assessment of changes based on the potential influence of the change on the quality of the final API. Factors such as where in the API synthesis the change occurred were taken into account. This recommendation used a decision tree as the device for determining filing status for changes and introduced the concept of the "last true solution" as a key factor in assessing potential risk and hence filing requirements.
While drafting its BACPAC guidance, FDA released a guidance for postapproval changes (3), which included the scientifically sound premise of establishing filing requirements for a change based on the potential for an adverse effect on the identity, strength, quality, purity, or potency of the product. This "Change guidance" used the "final intermediate" (i.e., the last compound synthesized before the reaction that produces the drug substance) as a key point in assessing API risk and filing requirements. Subsequently, FDA revised its guidance for postapproval changes (4), hereafter referred to as the Changes guidance. Nonetheless, PhRMA noted several provisions in that guidance lacked validity when applied broadly; for example, that a PAS is required for:
In February 2001, FDA released its BACPAC I guidance (1), which provided guidance on the filing categories and recommended supporting data for API changes up to and including the manufacture of the final intermediate. Several general considerations were cited in that document that supported opportunities for regulatory relief. For example, it was recognized that "the risk of adverse change is generally acknowledged to be greater when a modification occurs near the end of a drug substance manufacturing process rather than the beginning." Accordingly, under BACPAC I, it is allowable to file certain early-stage synthesis changes as changes being effected in 30 days (CBE-30), rather than as PAS. BACPAC I also indicated that "the final intermediate was chosen as the break point in this attempt to categorize risk because ... physical properties of the drug substance will not be affected by changes made up to that point." PhRMA proposes herein, as it did in its 1998 article, that physical properties of the drug substance will not be affected by changes before the "last true solution" (i.e., the processing point at which the drug substance is completely dissolved for the last time), assuming chemical comparability before and after the change. Therefore, this new break point offers a logical and scientifically sound basis for an assessment of potential risk further downstream from the final intermediate and, therefore, offers an additional opportunity for further regulatory relief. This point will be key to the following discussion about process changes. In addition, we present proposals related to site and specification changes that provide clarity to many everyday situations that are not addressed clearly in the current guidance.
Discussion of the decision tree
The PhRMA Working Group proposals for BACPAC II relate to three elements of the decision tree: site changes, specification changes, and synthesis or process changes.
Site changes. The provisions for reporting API manufacturing site changes for the steps from the final intermediate through the finished API, as contained in the Changes guidance, are appropriate for inclusion into a BACPAC II guidance. It is appropriate to report manufacturing site changes in a CBE-30 supplement. Only changes involving sites that have not been FDA-qualified (i.e., those have not been FDA-inspected or are found not to be CGMP-compliant) should require a PAS. The assumption is that the manufacturing-site change does not also involve changes to the manufacturing process or specifications. If multiple changes are involved, then the filing should be in accordance with the most restrictive individual changes, as is current practice.
The only deviation from the Changes guidance lies in a site change for analytical testing. If a CGMP-compliant site has transferred methods in accordance with agency guidelines, including cross validation, then both a science-based assessment and a risk assessment would suggest that the potential for adverse impact is minimal and that such a change should be handled as an annual report rather than as a CBE-30. Figure 1 shows the site change section of the proposed decision tree, and Table I compares current and proposed site-change requirements.
Figure 1: The "site changes" element of the proposed decision tree. Abbreviations: PAS denotes prior approval supplement, and CBE-30 denotes changes-being-effected in 30 days.
Specification changes. BACPAC II will cover all changes to the final intermediate specification, specifications for starting materials, reagents, raw materials, and solvents used in the process after the final intermediate and the finished API specification. Specification is used in this article in a broad sense, in accordance with the FDA definition, to include tests, analytical procedures, and acceptance criteria. As in BACPAC I, the authors encourage FDA to include the changes to controls of critical steps (e.g., test for monitoring critical reaction progress or for control of critical reaction events) in the scope of this section of the guidance.
Although FDA's Changes document provides guidance in this area, the attempt to address the wide spectrum of raw material, drug substance, and drug product issues in a single document renders that document cumbersome. PhRMA believes that the proposed decision tree provides needed clarification, while, in certain cases, providing for a lesser reporting burden without the potential to negatively affect API quality assurance.
In the proposed decision tree for specifications (see Figure 2), the first decision point is whether the change is being made to comply with a change in compendial requirements. We propose that all changes made to comply with an officially recognized compendium can be made in an annual report. Although this represents a deviation from the Changes guidance, it does correlate with the FDA's position as presented in the Federal Register notice (5) regarding enforcement discretion on this issue.
Figure 2: The "specification changes" element of the proposed decision tree. Abbreviations: PAS denotes prior approval supplement, and CBE-30 denotes changes-being-effected in 30 days.
The second decision point is highly critical. It calls for determining whether the change can provide the same or better quality assurance for the intended purpose. If such ensurance cannot be demonstrated and clearly documented, then the change should be submitted in a PAS. This is consistent with the current Changes guidance that correctly categorizes the risk of these changes as having a substantial potential to have an adverse effect on quality.
The next decision point focuses on changes to an alternate analytical method that provides same or better quality assurance. In accord with current guidance, such changes can be filed in an annual report.
Proceeding through the decision tree, one must next assess whether the change is to an analytical method only with no change to acceptance criteria. If so, one looks at the risk associated with the change to determine the filing mechanism. Examples of low-risk changes include reasonable changes in the operating conditions or minor modifications in operating detail such as sample preparation or the determination of system suitability. These changes are generally reported to ensure alignment of the registration dossier with current operating practice, which may have been altered, within acceptable limits, to account for factors such as column-to-column or equipment variability over time. Therefore, PhRMA proposes these changes be reported in an annual report.
If the change is beyond one of minor method detail, it must be determined if the method change involves the "regulatory analytical method" for the API. This criterion recognizes that changes to the final API regulatory analytical methods present somewhat greater risk than changes to analytical methods for the crude API, final intermediate, solvents, starting materials, and reagents. Therefore, PhRMA recommends that changes to the API regulatory analytical procedures be placed in the CBE-30 category and that other analytical method changes be placed in the CBE filing category. It must be remembered that all such changes have already passed the criterion of same or increased level of quality assurance.
This differentiation provides for a greater FDA oversight of changes to API regulatory analytical procedures by allowing time to review at least summary data and yet allowing for efficient implementation of equivalent or superior analytical methods. This type of regulatory relief would greatly assist in allowing industry to modernize analytical methods without the unnecessary burden of a PAS as currently mandated by the Changes guidance.
On the other major branch of the decision tree, one must analyze specification changes other than analytical method changes. First, one must address cases in which the specification change involves tightening or adding an acceptance criterion. These changes may be the result of improved process capability resulting in minimal risk and should be allowed in an annual report. As with all method and specification changes, it is expected that validation of new methods and any proposed new acceptance limits would be consistent with current guidance (e.g., International Conference on Harmonization [ICH]). Other cases may not involve tightening or adding specifications, and potential impact on API quality should be addressed. Such cases may involve the elimination of certain tests. Elimination of tests may, on initial glance, seem to fail the "same or increased level of quality assurance" criterion, but there are numerous examples in which eliminating a test does not affect quality assurance; for instance, the removal of a residual solvent test for a solvent no longer used or the elimination of a redundant test as in the case of multiple identification tests. Another example is the revising (widening or shifting) of acceptance criteria associated with an improved analytical method (e.g., thin-layer chromatography to high-performance liquid chromatography, in which assay methods may not have the same acceptance criteria).
If such changes involve the finished API specification, then the change should be filed as a CBE-30. Specification changes for the final intermediate and other materials would warrant a CBE filing. Again, this approach would allow FDA time to review summary data for changes to the API specification and ensure that the same or increased level of quality assurance has been demonstrated.
The proposed decision tree provides a logical path for determining a filing category for any specification change. To supplement this tool, Table I provides some examples of these types of changes and their filing categories under the current Changes guidance and the proposed flowchart for easy comparison.
PhRMA believes there is opportunity for FDA to provide regulatory relief in changes to specifications at and after the final intermediate by limiting the requirement for PAS to changes that are not demonstrated to provide the same or increased level of quality assurance. This regulatory relief would allow industry to easily implement improved analytical methodology and modernize specifications, thus improving overall product quality assurance.
Synthesis and process changes. PhRMA acknowledges the general considerations presented in BACPAC I such as the risk for adverse effects increases as changes are made later in the process as opposed to earlier. We also understand that this is the basis for the provision in the Changes guidance that requires a PAS for "any process change made after the final intermediate processing step in the drug substance manufacture." Understandably, late-stage changes offer fewer opportunities to remove or reduce impurities by means of purification and also present the potential to introduce changes in the API's physical properties. Nonetheless, PhRMA believes that this is an overly conservative position, particularly in light of today's regulatory climate that stresses innovation and quality improvement while incorporating new techniques in risk assessment. Accordingly, PhRMA believes that there exist considerable opportunities for changes after the final intermediate that should not represent a significant risk to product quality. The decision tree presented in Figure 3 outlines PhRMA's proposal for synthesis and process BACPAC II changes.
Figure 3: The "synthesis or process changes" element of the proposed decision tree. Abbreviations: PAS denotes prior approval supplement, and CBE-30 denotes changes-being-effected in 30 days.
Changes in the synthetic pathway (i.e., changes involving different isolated or in situ intermediates, including salt forms) between the final intermediate and the drug substance represent a reasonable risk that the quality of the drug substance may be adversely affected. Because these changes involve various process chemistries, it is not unreasonable to assume that new or greater levels of impurities might arise with limited opportunity to remove these in subsequent purifications. Such changes should be submitted as a PAS with appropriate documentation to support either the comparability of the purity profiles or the changes in quality (i.e., specification changes) that would continue to represent the safe use of the product.
Process changes may comprise changes in operating conditions and parameters, changes in reagents and solvents, significant changes to equipment, and the addition or modification of a rework procedure. Changes in scale, provided that stoichiometry is preserved, should not need to be submitted to the agency. Similarly, the addition of a reprocessing step after the final intermediate should not require submission. Reprocessing has most recently been defined in ICH Q7A (6) and a fairly thorough discussion of PhRMA's position on this topic appears in the literature (7). Likewise, changes to equipment of the same operating principle should have no regulatory effect.
Table I: Comparison of change-filing categories under current guidance and proposed BACPAC II decision tree.
For all other post–final intermediate process changes that are not consistent with new drug application (NDA) process description, the manufacturer must evaluate the postchange material versus the prechange material. That evaluation must include a comparison of chemical quality and relevant physical properties. In either case, one must assess whether the current analytical methodology is adequate to properly determine the quality effect of the change. Many older products may continue to use methodology that is less discriminating than currently available techniques and standards to detect changes in API quality. For example, a regulatory method for impurities by high-performance liquid chromatography may not have been validated for all impurities according to the International Conference on Harmonization identification thresholds. If appropriate methods are not available, they should be developed and applied in the change assessment. Such modifications to existing regulatory methods should be filed in the NDA according to the decision tree for specification changes found in Figure 2. Nonetheless, it may be reasonable in some cases in which additional methods are used and reported for nonroutine comparability assessment that these methods should not need to be added to the API's routine quality standards.
Once appropriate methodology has been identified for the physical and chemical assessment, one must be assess whether the change occurs before the operating stage at which the drug substance (or an in situ precursor) is completely dissolved for the last time, including a required final recrystallization step. This point, referred to herein as the last true solution (LTS) represents an additional opportunity in the process to assess risk. Changes made at or after the LTS will arguably bear more risk of adverse quality effect than changes made before it because of the limited opportunity for subsequent quality enhancement. In addition, because it is only after the LTS that physical properties are determined, changes made at or after this point may affect those attributes as well. To stress PhRMA's position again: Changes that have no impact on the NDA process description, changes to equipment of the same operating principle, and the addition of a reprocessing step do not have any regulatory effect and are not considered under this provision. Therefore, the overall risk of adverse effect resulting from a change after the LTS may be considered as significant and requires a PAS.
Conversely, changes made before the LTS will not affect physical properties and will have less potential negative influence on the drug substance's chemical properties because of the purification affected by subsequent operating steps, including that of the LTS. For example, a final intermediate may be a carboxylic acid ester. A change may be made to the hydrolysis process that generates an ionic salt, which may be isolated, solubilized, neutralized, and isolated as the crude carboxylic acid API. This crude material may be recrystallized (by means of the LTS) and isolated in pure form. In this case, at least two operating steps and two solution steps separate the change from the API. Therefore, the potential risk for adverse effect is moderate at best and would warrant only a CBE-30 filing. Though a level of risk potential may be assigned categorically, there must always be a comparative quality assessment pre- and postchange. If there is the same or greater level of quality assurance (i.e., no new impurities or greater amounts of existing impurities according to the rigorous criteria set by ICH Q3A), then the moderate risk potential is supported, and the change may be filed as a CBE-30 (8). If new impurities exceed ICH Q3A thresholds or if the amounts of existing impurities exceed current specifications (i.e., limits of qualification), then a PAS should be filed.
The PhRMA positions on BACPAC II changes contained in this article represent a pragmatic approach to the management of changes in the API process after the final intermediate. The decision trees presented offer a clear and scientifically sound approach to assessing potential risk and to using pre-and postchange comparative quality assessments to supplement that risk assessment. In doing so, several opportunities have been identified for regulatory relief, without negative effects on quality or public safety. Table I compares the filing requirements under current FDA guidance with those proposed in this article. Under this set of proposals, prior approval supplements for changes after the final intermediate would be limited to changes to non–FDA qualified sites; specification changes that do not provide the same or increased level of quality assurance; synthetic route changes; and process changes for which comparable physical and chemical properties cannot be demonstrated. These proposals would offer significant advantages to API manufacturers in allowing timely implementation of late-stage process improvements that could have substantial positive effects on API quality, cost, and productivity.
The development of this position paper was supported by members of the BACPAC Working Group under the guidance of the PhRMA API Technical Group. In addition to the authors, members of this group included Charles Aiman (formerly of Aventis), Lois Atkins (Lilly), Robert Clark (Novartis), John Donabauer (Abbott), Denise Flanagan (Pfizer), Ralph Hodosh (Abbott), Donna Kapples (Novartis), Joan LaFollette (BMS), Jack Manis (Pfizer), David Mitchell (AstraZeneca), Michael Mitchell (Schering-Plough), Suva Roy (Otsuka), Dhiren Shah (formerly of Aventis), Joseph Timko (Pfizer), and Jean Wyvratt (Merck).
John Curran is the Director of Regulatory and Analytical Services—CMC, Merck & Co., Inc. (West Point, PA). Wendy Mavroudakis is the Director of Global Regulatory Affairs, Chem-Pharm, Johnson and Johnson Pharmaceutical Research and Development, LLC (Titusville, NJ). Dave Ridge* is the Group Director of Drug Regulatory Affairs, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, tel. 973.562.3696, fax 973.562.3700, email@example.com
*To whom all correspondence should be addressed.
1. US Food and Drug Administration, Guidance for Industry–BACPAC I: Intermediates in Drug Substance Synthesis (FDA, Rockville, MD, Feb. 2001).
2. J. Wyvratt, PhRMA Bulk Active Postapproval Changes (BACPAC) Decision Tree, Pharm. Technol. (9), 68–76 (1998).
3. FDA, Guidance for Industry—Changes to an Approved NDA or ANDA (FDA, Rockville, MD, Nov. 1999).
4. FDA, Guidance for Industry—Changes to an Approved NDA or ANDA (FDA, Rockville, MD, Apr. 2004).
5. "Guidance for Industry on Changes to an Approved New Drug Application or Abbreviated New Drug Application; Specifications—Use of Enforcement Discretion for Compendial Changes," Fed. Regist. Nov. 22, 2004 (69 FR 67930)
6. FDA, Guidance for Industry—Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (FDA, Rockville, MD, Aug. 2001).
7. M. Mitchell, "PhRMA Perspectives on Drug Substance Regulatory Issues: Starting Material, Reprocessing, Retesting, and Critical Controls," Pharm. Technol. 27 (2) 34–52 (2003).
8. FDA, Guidance for Industry—Q3A Impurities in New Drug Substances (FDA, Rockville, MD, Feb. 2003).