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This series is intended to address the challenges for the industry to comply with pharmacopoeial requirements. This article returns to this important topic with a case study at the intersection of monograph development and compliance.
Previous articles in this series detailed the monograph development process, which is accomplished through partnership between the bio/pharmaceutical industry and the pharmacopoeias (1,2). Rationale was provided to help companies decide whether they will participate in the process as a potential advocacy opportunity for the company through monograph development for their drug substances and products. In a broader context, however, the overall series of articles is intended to address the challenges for the industry to comply with pharmacopoeial requirements. This article returns to this important topic with a case study at the intersection of monograph development and compliance.
The drug product lifecycle described in the first article of this series (3) provides context that is helpful for considering compliance challenges. A company initially discovers a new drug substance and develops it into a drug product, performing clinical studies to ensure it is safe and effective. During development, the company establishes standards of quality that are considered appropriate for the drug substance and product. When all the necessary drug development information is available, it is submitted to regulatory agencies to gain marketing approval for the product in countries around the world. During the regulatory review process, differences can emerge in the quality requirements that are approved for the product, based on determinations made by the health authorities in individual countries. These differences are often minor, but may also be quite significant, creating challenges for compliance in all countries where the product is approved.
An extreme, but not uncommon, example can be imagined for a drug product that contains a genotoxic impurity. Differing views by different regulators as to the appropriate control for this impurity can lead to more than 20 different country-specific limits for the impurity. The company can then test and release the drug product to the individual limits that are approved in each country. A more common approach, however, is to apply the tightest approved limit to enable worldwide release of the product. Even with this global approach, individual certificates of analysis are required to reflect the approved limits in individual countries. Continuing several years further in the product lifecycle, the pharmacopoeias eventually develop monographs for the drug substance and product, which can introduce additional differences in testing requirements.
Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable (3). The situation is even more complex because a company must comply with the pharmacopoeial requirements that are applicable in a particular country, and also with their product registrations as approved in countries around the world. There are many challenges that make pharmacopoeia compliance difficult, including the need to address differences between the pharmacopoeia and approved registrations (4).
There are reasons why a company might choose to proactively submit information to the pharmacopoeias to enable monograph elaboration, but different companies may make different decisions (1). One option is for the company not to participate in the process, due in part to the difficulty in resolving differences that may emerge in the pharmacopoeia monograph; the later the monograph is developed, the longer the company can defer addressing the differences. These differences in the monograph, compared to the requirements contained in the product registrations, occur even though the monograph is usually based on specifications that are approved by regulatory authorities, as stated in the Good Pharmacopoeial Practices (GPhP) guidance (5). Differences between the monograph requirements and the registrations must be resolved so the company remains in compliance. There is some flexibility in how the company complies, with a range of options to resolve the differences, but in this flexibility, there is also complexity.
Another choice a company might make is to participate in monograph development, but to submit the necessary information when multiple companies are involved in the process. This may be considered an intermediate approach, based on the timing for the submission, which still may result in compliance challenges if the monograph differs from the company’s approved registrations (1).
At the other end of the range of choices is proactive participation early enough that the company is the only one involved in the initial elaboration of the monograph, reflecting their position as the only company with regulatory approval at that time. One of the benefits of this approach is the possibility of developing a monograph that is harmonized across multiple pharmacopoeias. Even when a company chooses to participate, there will likely be differences between the resulting monograph and the approved registrations. These differences may be understood in the transition from a “private” standard applicable to that company alone, to the “public” standard contained in the monograph. Knowing why the differences emerge, however, does not make it any easier to address them and ensure ongoing compliance.
In the example provided here, the impact of the publication of a new monograph in the pharmacopoeia is explored, based on the experience of one of the authors (6). Although the perspective is that of an innovator company, the information helps explain the compliance challenges experienced by all companies across the broader bio/pharmaceutical industry. The impact of a new monograph depends, to some degree, on the answer to the following question: which came first-the pharmacopoeia monograph or the regulatory approval? For an innovator company, the approval comes first, typically by many years, and the resulting impact of the monograph is due to differences between the newly published monograph and registrations that have been approved for many years. It is important to note that the differences are in the specifications-the tests, methods, and acceptance criteria-for the drug substance and product that are the subject of the monograph. The drug substance or product do not typically change after the monograph is published, rather the quality filter, or lens, through which the material is evaluated has been changed. If differences in the monograph are significant enough, the challenge of complying with the requirements published in the pharmacopoeia may become so difficult that the company may be forced to take the product off the market. This is clearly not in the best interest of patients who may rely on the medicine.
If the monograph in the pharmacopoeia is supposed to reflect the requirements in the approved registration, why should there be any differences? The answer lies in the practical basis of converting the approved registration, which is used by a single company, to the public standard in the monograph that will be used by all companies who manufacture and market that drug substance and product. In the authors’ experience, 80% or more of the compliance challenges are related to differences in the control of impurities. According to the International Council for Harmonization (ICH) Q3A (7) and Q3B (8) guidance documents, an organic impurity in a drug substance or product is either specified, meaning it is individually listed and limited with a specific acceptance criterion, or unspecified, meaning it is limited instead by a general acceptance criterion. For the innovator company who developed and validated the analytical procedure used to control impurities in a drug substance, a specified impurity may be identified by a relative retention time (RRT) in the chromatogram, based on standardization of the column and equipment used across the company. The use of RRT to identify the specified impurity becomes problematic when the method is incorporated into the monograph, since equipment and column standardization are no longer guaranteed. Any analyst who has run a chromatographic procedure recognizes the differences that may be observed, for example, when using different C-18 columns, as allowed in monograph methods.
To address this challenge in identifying a specified impurity, the pharmacopoeias often require that a reference standard be available that enables unequivocal confirmation that an observed peak corresponds to the specified impurity. In many instances, the company that developed the chromatographic procedure does not have a sample of the specified impurity to provide to the pharmacopoeia to establish the reference standard. Also, the company may not have a “dirty batch” of the drug substance that would include the specified impurity and enable identification for the corresponding chromatographic peak. In this situation, taking into account the current process-capability and stability data, the pharmacopoeia may determine that the specified impurity must instead become an unspecified impurity, potentially resulting in a significant tightening of the limit compared to the approved registration. A related challenge that applies to the drug product is determining whether an impurity peak observed in the chromatogram for the product corresponds to a degradation product or is instead, a process impurity from the drug substance. This issue makes it difficult for the monograph to reflect the principle in ICH Q3B that only degradation products need to be controlled in the drug product, and not drug substance process impurities. Another significant difference and compliance challenge can result if the company has developed two different methods for assay and impurities in the drug product, or different methods for different product formulations or strengths, whereas the pharmacopoeia determines that a single method may be used for impurities and assay across the entire product line.
Other differences may emerge in the monograph, which seem to be less impactful than that experienced with impurities. However, the steps necessary for a company to address these differences in their quality documents and regulatory filings can still pose significant challenges. An example is the addition of a new identity test in the monograph, such as infrared (IR), to complement a chromatographic identity test for the drug substance to ensure that all stakeholders who use the monograph can demonstrate unequivocal identification of the active ingredient. Another example is the widening of an assay limit for the drug substance to reflect appropriate analytical variability. Other examples include modifications to the chromatographic procedure, perhaps adding an isocratic hold at the start of the run to address dwell volume, which will also impact peak retention times, or the addition of new requirements to ensure acceptable system suitability for the method, such as peak resolution. As will be shown later, these changes range from minor to major impact when exploring the options of how to resolve the differences and ensure compliance with the monograph and the registration. The differences will likely impact quality documents and testing performed in the laboratory, with duplicate testing of the same quality attribute as the worst-case outcome to comply with the registration and the monograph. Depending on the company’s compliance strategy, the differences may also impact product registrations, requiring updates or variations in countries around the world.
Some requirements in the monograph may be very difficult to meet (e.g., tighter impurity limits). If the monograph has already been published as official, another possible approach to resolve differences is communication with the pharmacopoeia to request revision of the monograph to better align with the registration. However, the pharmacopoeia revision process can be slow and is not always successful in achieving the requested changes. The probability of successful revision is also reduced if the company did not provide comments and concerns to the pharmacopoeia when the monograph was first proposed. This points, once again, to the benefit of proactive surveillance of pharmacopoeia updates with an appropriate response at the proposal stage (9). Not only does this provide the company an opportunity to possibly influence the requirements before the monograph becomes official, but it also enables internal discussion to plan for implementation of the requirements in the new monograph, when it does become official.
This situation, emphasizing the challenge of resolving differences between a new monograph in the pharmacopoeia for a drug substance or product and the information included in product registrations approved by regulatory agencies around the world can best be understood through an illustration that follows the product lifecycle. Figure 1 represents the situation for an innovator company before the monograph elaboration process has been initiated. The smaller arrows represent regulatory approvals received in various countries. Currently, the regulatory submission and approval often occurs first in the United States and Europe (covering 30 countries, when following the “centralized procedure” of assessment by the European Medicines Agency [EMA]). At this point in the product lifecycle, the approved registrations in the US and Europe are generally aligned, although there may be differences based on decisions by the regulators for one of the applications, such as revising an impurity limit from “not more than 0.1%” to “not more than 0.10%”, which tightens the limit based on generally accepted rounding rules for scientific data. The next submission might go to the Japanese health authority, with approval granted with some additional changes. The additional differences may be minor, such as the requirement to use six injections rather than five to establish the percent relative standard deviation (%RSD) for a chromatographic procedure. The arrow for Japan in Figure 1 is intended to show that some divergence is starting to emerge in the approved registrations. The next approval might come in China, again with the possibility of some differences compared to the approvals in the US and Europe. The drug applications continue, going next to a country designated as “Most of World #1” (“MOW #1”) and continuing to “MOW #10” and “MOW #150”. The arrows for these countries are intended to convey that the approved registrations in 150 or more countries are generally aligned, despite some differences. This is represented overall by the larger arrow, indicating at this point that the methods and limits in the quality standard (QS) may be used by the company to test the product and ensure compliance with the product registrations approved in 150 or more countries. Also at this point, the registrations and QS follow the typical process for updates and renewals to reflect subsequent regulatory requirements and manufacturing or analytical changes for the material.
The large aqua arrow in Figure 2 summarizes the situation for the US, Europe, and MOW #150 countries, with the fundamental direction emphasizing the global alignment and necessary compliance with approved product registrations. This figure, however, extends the product lifecycle to include the point of monograph elaboration. In the prospective harmonization pilot project referenced in a previous article (1), the United States Pharmacopeia (USP) and European Pharmacopoeia (Ph. Eur.) monographs were developed at the same time, and a harmonized outcome was achieved through the collaborative process. Many of the requirements in the harmonized monographs were aligned with the product registrations. However, the monographs also contained some differences from the registrations that were significant enough to make compliance with the new requirements difficult. This is indicated by the small red and blue arrows in Figure 2, which are pointing in a slightly different direction than the aqua registration arrow. Among the differences were significant changes to the chromatographic procedure used for assay and impurities, as well as tightening of impurity controls, changing a previously specified impurity to an unspecified impurity with a new limit of 0.10%, because there was no practical way to identify that impurity peak in the chromatogram. The impact of these changes goes well beyond the US and Europe, because regulators in many countries around the world look at the USP and Ph. Eur. monographs as quality standards that must be met for medicines in these countries. The monograph situation in the figure becomes more complicated as other pharmacopoeias, such as those in Japan (Japanese Pharmacopoeia [JP]) and China (Chinese Pharmacopoeia [ChP]), subsequently develop their own requirements, which may differ from the USP and Ph. Eur. monograph, if not harmonized. Ultimately, there may be as many as 40 different pharmacopoeias that contain monographs applicable to the drug substance or product (10). The overall picture for pharmacopoeias is represented by the large purple arrow, which is not fully aligned with the large aqua arrow for product registrations.
At the point when the pharmacopoeia monograph has been published as official, companies must comply with the new requirements contained therein, in addition to complying with their approved registrations. The question is how a company can resolve differences and ensure alignment with both the monograph requirements and the registrations. The answer is that this is done through modifications to testing procedures and limits in the quality standard and/or updates to the product registrations. It must be recognized that implementing these changes can have significant impact on available resources, either performing additional testing or submitting updates to 150 or more registrations around the world.
It is incorrect for a company to assume they do not need to comply with the monograph just because they have a separate regulatory approval (4). Regulatory agencies around the world expect compliance with the requirements in the pharmacopoeia, including new monographs, that are applicable in their country. This is well understood, for example, in Europe and in Japan where it is known that compliance with the new monograph is required. It is not as well understood, but equally true (3), that FDA requires compliance with the USP monograph as mandated in the Federal Food, Drug, and Cosmetic Act. The challenge becomes how to resolve differences between the monograph and product registrations.
In some cases, the monograph may include differences in acceptance criteria for certain tests when compared to the approved registration. The practical basis for these differences was discussed above. The monograph limits may be either tighter or wider, and the available options to ensure compliance are either to adopt or not to adopt the different limits in the monograph. However, the choice is not quite as flexible as suggested by this statement. Recalling that a company must comply with the approved registration and the monograph, if the monograph limit is tighter than that listed in the registration, then the tighter limit must be applied going forward to ensure compliance with the monograph. It is possible that a company may have difficulty meeting the tighter limit, which may necessitate communication with the pharmacopoeia regarding possible revision to the monograph, or discussion with the regulatory agencies about possible approaches to ensure the product will continue to be available for patients.
If the monograph limit is wider (e.g., the assay limit has been widened to reflect analytical variability), then a company can choose to apply the wider limit, but this requires updates to registrations with regulatory approval needed in 150 or more countries to allow the use of the wider criteria, even though this is listed in the pharmacopoeia. Different limits will be required in different countries if some of the regulators do not approve the registration updates. Alternatively, the company may choose not to apply the wider limits, which may seem somewhat counterintuitive. Maintaining the tighter limits as approved in the registration, however, rather than switching to the wider monograph limits means no updates would be needed to the registrations. Meeting the filed limits, which are tighter, obviously ensures compliance with the wider limits in the monograph. This approach requires no work by the company’s regulatory group, but it could have major impact to other groups, including quality and supply. One situation showing the impact of maintaining the tighter limits is a source of supply change, shifting from internal manufacture of the drug substance to an external partner, or from one external partner to another. The company must now insist that the contract manufacturer meet the tighter limits in the registration, rather than the wider limits in the monograph (which would be suitable for all other customers). This results-at best-in higher cost paid by the company for the material or-at worst-the inability for the company to obtain material meeting the tighter limits, with the obvious impact on supply of the medicine.
As noted previously, there is some flexibility in how a company chooses to comply with the monograph and registrations. However, in considering differences in analytical methods, the range of options is limited and includes the following: Merge, Add, Replace, or Keep. These choices can be denoted as the “MARK” principle (Table I), and the decision of which to apply will depend on the specific situation and the level of risk a company is willing to take. The most appropriate option often becomes clear when considering how significant the analytical method differences are. This is detailed below, with an indication of the potential impact to the analytical procedures and to the product registrations.
Merge. The “merge” approach to compliance involves incorporating or merging any additional requirements from the monograph into the testing already performed by the company per the approved registration. This approach is generally applicable to minor method differences, such as additional system suitability criteria listed in the monograph beyond what is currently done. The additional criteria for a chromatographic procedure may include peak symmetry, resolution, or tightening of the %RSD for multiple injections. It would be difficult to defend a decision not to include these additional criteria since they are intended to demonstrate that the method is suitable to provide a valid result. If the laboratory can meet the additional system suitability criteria, they may be simply merged into the existing analytical procedure used for quality testing. If the criteria cannot be met, then discussion with the pharmacopoeia may be necessary for guidance on how to comply with the criteria, or to consider a change to the criteria in the monograph method to reflect the laboratory’s experience. No update to the procedure in the product registration is necessary with the “merge” option because the company is still complying with the requirements already approved by the regulators, and doing even more by complying with the additional criteria in the monograph.
Add. In elaborating the new monograph, the pharmacopoeia may introduce an entirely new test and analytical procedure to ensure appropriate quality for the material. The new method may also be added to ensure consistency with the testing typically requested in the pharmacopoeia technical guides for monograph content. A simple example of this is the addition of a new test in the monograph to ensure the identity of the drug substance. For the innovator company, identification for the material can often be assured through manufacturing process controls, so the approved registration may include only the chromatographic retention time for the main peak to identify the drug substance. When the quality standard in the monograph is developed to apply to materials from other manufacturers, with possible testing by second or third parties, additional assurance of identity may be needed. The additional test may include an IR identification or confirmation of the counterion in a drug substance that is a salt. The appropriate option in this situation is likely to “add” the new test to the quality standard, increasing the workload in the laboratory. Again, no update to product registrations is necessary because the current testing still ensures compliance with what is approved; there is now additional testing beyond the registration and no compliance gap. An alternate decision in this scenario is for the company not to add the new monograph method, given the process controls for the material. There should be technical justification to document that the material “will pass if tested”. In this risk-based approach, the company would not necessarily need to file this justification, but it should be available on inspection if regulators ask how the company ensures compliance with the additional test in the monograph.
Replace. Some monographs may introduce a procedure that is significantly different than what is included in the approved registration. A challenging example of this is a chromatographic procedure for assay and impurities that is significantly different than what is registered. This situation may arise for several reasons, including the preference by the pharmacopoeias to specify a single method for assay and impurities in all monographs covering the drug substance and the entire product line. At the time of monograph elaboration, this preference makes sense to standardize the test method in the public standard across the product portfolio. Considering the earlier stages in the product lifecycle, however, this approach is typically not reflected in a company’s approved registrations, because the development of the drug substance, followed by the initial formulation of the drug product, and the subsequent introduction of other strengths and dosage forms occur over several years.
In this case, the company’s compliance choices are either to “replace” the test method currently approved in the registration with the monograph method or to “keep” the approved method instead of the monograph method. Either of these choices requires a laboratory demonstration of equivalency between the currently approved method and the new monograph method to ensure compliance with both. This equivalency data can be used to justify the company’s decision, either upon submitting an update to the product registration or upon inspection of the manufacturing and testing facilities by regulators. The equivalency evaluation requires allocation of laboratory resources, creating challenges due to competing priorities. However, this one-time activity to document the equivalency outcome can help minimize the impact to the company for ongoing, routine testing. On the other hand, if the methods cannot be demonstrated to be equivalent, then a company might instead have to default to the “add” option, running both test procedures to ensure compliance with the registration and monograph. Alternatively, data showing the methods do not give equivalent results may be provided to the pharmacopoeia with a request to revise the procedure accordingly.
Compared to the somewhat limited impact to the testing laboratory, the choice to “replace” an approved method has the opposite impact on product registrations. Switching from a test method that has already been approved by regulatory agencies requires updates to the product registrations to justify the switch from the currently approved method to the monograph method. This can have a significant impact on the resources in the company’s regulatory/chemistry, manufacturing, and controls (CMC) functions.
For one large, multi-national company that was involved in the prospective harmonization pilot project, the decision to replace the approved method with the monograph method required the submission of registration updates and variations in more than 150 countries (6). Indeed, the company made the decision to adopt the harmonized monograph in its entirety-the tests, methods, and acceptance criteria-replacing the detailed information previously included in the registrations. Not only was this time-consuming on the front end, the registration updates began a process that took several years to complete, with different timelines for review and approval in different countries. As the regulators in some countries began to approve the registration update, the review process in many other countries had not yet been completed.
This created a compliance issue in the interim, with the adoption of the monograph approved in some impacted countries, but not yet in others. How can a company comply with both the monograph and existing registrations during this transitional period? One option is to perform testing using both methods until all approvals are received, with obvious impact on the laboratory. Another option is to continue to use the currently approved methods until a fixed implementation date or until approvals are received in key markets, then switching over to the monograph methods, while still waiting for approval in the remaining markets. This approach carries some risk in ensuring compliance with both methods, but relieves the laboratory from having to perform duplicate testing in the interim. The compliance risk can be mitigated by the documented equivalency between the two methods, mentioned earlier. Another compliance risk can emerge if the regulators in one country reject the updated registration, forcing the company to continue duplicate testing to ensure global compliance and release of the product to all countries.
Given the range and nuance of compliance challenges associated with the “replace” option, it is clearly important that all impacted stakeholders across the company, including analytical, quality, and regulatory, work together to develop and align on the strategy and then execute the implementation plan for adopting the monograph, while ensuring compliance with product registrations. As noted previously, despite the challenges, one benefit of the “replace” option is that the company can remove many of the details of the analytical methods from the registration to refer instead to compliance with the monograph. This simplifies the information detailed in the registration and enables the company to more easily implement subsequent revisions to the monograph, which ensures ongoing compliance with “current pharmacopoeia requirements”, as expected by regulatory agencies around the world (3).
Keep. The other option, with a significantly different method in the monograph compared to the approved registration, is to “keep” the currently approved method instead of switching to the monograph method. There may be a strong preference for a company to continue using an analytical procedure that has been used for many years to ensure the quality and stability of the drug substance and product. Again, the equivalency of the approved method and the monograph method must be demonstrated. The General Notices in most pharmacopoeias allow the use of alternative methods that are equivalent or better than those in the monograph. Because of this, for most countries, there would be no need to update the product registration if the decision has been made to keep using the currently approved method instead of the monograph method. The demonstration of equivalency would be shown upon facility inspection, if requested, as evidence of compliance with the monograph requirements.
However, if the new or significantly different method is listed specifically in a monograph of the Ph. Eur., then submission of a variation is required in European countries that are members of the EMA or signatories to the Ph. Eur. Convention. The reason for this is the specific language in the Ph. Eur. General Notices (11) that states an alternative method may be used instead of one in the Ph. Eur., provided the alternative method ensures compliance with the monograph and the use of the alternative method has gained the “agreement of the competent authority,” meaning approval by the European regulatory agencies. In the authors’ experience, no other pharmacopoeia or regulatory agencies mandate this prior-approval before the alternative method can be used to replace a method in the pharmacopoeia. In the case of the publication of a new Ph. Eur. monograph, where a monograph did not previously exist, this regulatory approval for a company to continue using the previously approved method in Europe rather than a method in the new Ph. Eur. monograph is necessary, even though the company had previously received approval for their method in Europe. In essence, the currently approved method is now considered an alternative method to that in the Ph. Eur. monograph.
For the drug substance, there is another way to ensure European regulatory agreement to use methods other than those listed in the corresponding Ph. Eur. monograph. The procedure for “Certification of Suitability to the Monographs of the European Pharmacopoeia” (CEP), described on the European Directorate for the Quality of Medicines and HealthCare (EDQM) website (12), provides for a centralized assessment of applications describing the manufacture and quality control of drug substances to facilitate and simplify exchanges between regulators and industry to ensure compliance with the Ph. Eur. and therefore with the requirements of the relevant EU legislation. The procedure complements and bridges the Ph. Eur. monograph and the submission of a marketing authorization dossier for a drug product. Also as noted on the EDQM website, CEPs are recognized by the signatory parties of the Ph. Eur. Convention and are also recognized by many other countries around the world, including Canada, Australia, New Zealand, Tunisia, and Morocco.
Compliance with compendial standards is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable and is essential to ensure continued availability of medicines to patients. However, compliance is complicated when there are differences between compendial requirements and approved drug product registrations. Challenges may arise in the elaboration of monographs by the pharmacopoeia, when differences emerge in the tests, methods, and acceptance criteria-ranging from minor to significant-between the monographs and registrations. These differences must be addressed to ensure ongoing compliance. Options include the addition of more quality testing or updates to product registrations to bridge any gaps.
For method differences, the choices are limited, as expressed in the “MARK” principle: Merge, Add, Replace, or Keep. To achieve compliance decisions that meet both regulatory and compendial requirements, dialogue is needed between impacted stakeholders in a company, including quality, regulatory, compendial affairs, and many others. Aligning on an implementation strategy and maintaining communication throughout the execution of the plan are essential to achieve the best compliance outcome for the company.
The authors gratefully acknowledge the contribution of Susan J. Schniepp for her technical review and helpful suggestions during the preparation of this series of articles.
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