Joseph A. Albanese, director of Analytical Strategy and Compliance at Janssen Research and Development, LLC

Joseph A. Albanese

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. This fundamental principle is presented at the beginning of a series of 12 articles (1–12) published to increase the understanding of this far-reaching and complex situation and to give practical guidance on addressing pharmacopoeia compliance. The articles appear in three online Regulatory Sourcebook eBooks and can be accessed through a dedicated webpage (13) with individual links to each of the 12 articles.

The detailed information in the articles provide important compliance considerations for the bio/pharmaceutical industry, including innovator, generic-drug, virtual, and start-up companies who discover, develop, manufacture, and distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products.

This current article provides an overview and summary of key points from the series—in effect, a narrative table of contents—intended to bring greater awareness to the availability of the articles, which can help provide guidance for this important pharmacopoeia compliance work.

Why Pharmacopoeia Compliance Is Necessary

The first article in the series (1) provides the legal and regulatory basis for the fundamental principle of pharmacopoeia compliance in the United States, Europe, Japan, and many other countries, thereby establishing the foundation for subsequent articles in the series. The purpose and content of pharmacopoeias is presented, and it is noted that the pharmacopoeias impact drugs and their ingredients throughout the entire product lifecycle. Additional important points are also introduced: a company must comply with “current” pharmacopoeia requirements, meaning a company must monitor and implement updates published by the pharmacopoeias; and a company must comply with applicable pharmacopoeia requirements and also with their approved drug product registrations, so that a company must address the complexity of these compliance challenges. The information provided in the first article is useful for enabling engagement and discussion among the many stakeholders within a company who are impacted by pharmacopoeia requirements, ensuring a common understanding across the various functions, and helping to avoid the risks associated with non-compliance.

Why Pharmacopoeia Compliance Is Difficult

The second article (2) provides a comprehensive, end-to-end framework to help bio/pharmaceutical companies better understand the external and internal challenges that make pharmacopoeia compliance difficult. Among the external challenges are the lack of broad harmonization of pharmacopoeia requirements around the world and the significant number of new and revised requirements that are routinely published. Internal challenges for companies include the lack of broad understanding of the need for and the complexity of remaining compliant. Enhanced awareness provided by the second article can facilitate the establishment and maintenance of collaborative partnerships among internal stakeholders to help address the compliance challenges.

A Brief History of Pharmacopoeias: A Global Perspective

Today, there are as many as 40 pharmacopoeias published around the world. Their history, presented in the third article of the series (3), reveals a common purpose, which is to support the health of the population through consistent standards for medicines. Many, including the 

, were established to harmonize the content and remove inconsistencies between the various pharmacopoeias which then existed. Regional and international initiatives continue even today, with global pharmacopoeia standards being one potentially beneficial outcome. The global and historical perspective is helpful in understanding the complexity and challenges of pharmacopoeia monitoring and compliance.

Global Pharmacopoeia Standards: Why Harmonization Is Needed

Building on information in prior articles, the fourth article (4) provides some industry perspective on the benefit of harmonization or convergence of pharmacopoeia standards around the world. When the standards are not aligned, the differences increase the cost and complexity of compliance. The concepts of the “ideal pharmacopoeia” and “compendial globalization” are presented as potential models to help achieve consistent and appropriate quality requirements for medicines worldwide. Concluding the fourth article, readers are asked to imagine a world where there is no need for translation, because the pharmacopoeias are all saying the same thing. Global pharmacopoeia standards would help to support the availability of medicines with consistent quality for patients worldwide.

Harmonization Efforts by Pharmacopoeias and Regulatory Agencies

There are many pathways to achieve harmonization, and several approaches are currently underway. The pharmacopoeias and regulatory agencies around the world, in collaboration with their stakeholders, have been actively and successfully working toward harmonization for quite some time. The fifth article in the series (5) describes what has been achieved in this area so far and what is yet to come. Among the topics covered are the Pharmacopoeial Discussion Group and the International Council for Harmonization (ICH), with particular attention given to the ICH Q3 topic on impurities and Q4B on the interchangeability of selected pharmacopoeia text. Contributions of the World Health Organization are also described, which include their convening of the International Meetings of World Pharmacopoeias and the resulting establishment of Good Pharmacopoeial Practices to encourage harmonization of compendial standards. Also discussed is the successful collaboration between the bio/pharmaceutical industry and the pharmacopoeias to achieve prospective and informal harmonization of new monographs for drug substances and products.

Revision Process for Global/National Pharmacopoeias

As noted in the first article (1), a company must comply with “current” compendial requirements, which introduces the need to monitor and implement updates published by the pharmacopoeias. The revision processes used by the pharmacopoeias and their associated schedules for publication of proposed and official updates are detailed in the sixth article (6). Designating pharmacopoeias as either “global” or “national”, based on regulatory acceptance, can help give visibility to some of the differences between their processes. This in turn can assist individual companies in focusing their compendial work on those activities that help ensure compliance.

Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions

The surveillance process used by the industry is driven by the revision process and publication schedules of the pharmacopoeias. The seventh article in the series (7) takes a detailed look at industry processes to monitor the significant volume of changes published and to achieve on-time compliance with updated requirements. Monitoring the pharmacopoeia updates provides an opportunity to respond to proposed changes and provide input that may potentially impact the decision on whether and how the updates proceed. Practical guidance is presented in the context of a compendial affairs organization within a bio/pharmaceutical company. There is also an exploration of the additional people and tools necessary to establish effective, efficient, sustainable, scalable, and successful processes for addressing the challenges of pharmacopoeia compliance.

Monograph Development: Why and When to Participate

As noted above, responding to proposed updates in the pharmacopoeias provides an opportunity for a company to potentially influence the outcome. There is an opportunity for even more proactive advocacy through a company’s participation in the process to develop new and revised monographs. The eighth article of the series (8) presents many considerations to aid a company in determining whether or not to submit a monograph proposal. Additional considerations are provided on the most appropriate timing for a submission, from the perspective of both the pharmacopoeia and the company. The potential for achieving harmonized monographs is also discussed. The article makes it clear that the answers to these questions on monograph development may not be the same for all companies, or products in the portfolio.

Monograph Development: How to Participate; How to Harmonize

Having explored in the eighth article (8) the considerations of whether and when a company should submit a monograph, once decided, there are additional practical points to consider. These include how to navigate the process of working with a pharmacopoeia and how to approach prospective or informal harmonization of the monograph through collaboration with multiple pharmacopoeias. These additional points are described in the ninth article (9), which also includes detailed considerations of which groups in a company should have the responsibility to submit the monograph and what specific information and materials are necessary to support monograph development. Taken together, the eighth and ninth articles provide a comprehensive set of tools to enable a company to understand and successfully execute the monograph development process.

A Practical Approach to Pharmacopoeia Compliance

Compliance with pharmacopoeia requirements that are applicable in a particular country, and also with product registrations as approved in countries around the world, is a significant challenge for bio/pharmaceutical companies. Effectively addressing differences between the pharmacopoeia and approved registrations can be complex. The tenth article of the series (10) tackles the specific compliance challenge that occurs when a new monograph is published in the pharmacopoeias for a drug substance or drug product in the company’s portfolio. Possible options are provided to deal with differences in limits and methods between the monograph and the previously approved registration. This practical guidance can help a company align on the best overall compliance strategy for a given situation.

A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials

The tenth article (10) dealt with externally based compliance challenges, driven by decisions made by the pharmacopoeias during the monograph development process. There are other compliance challenges that are internally based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. One such example can be found with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment. This case study is explored in the eleventh article (11), with principles and strategies provided to help companies ensure compliance with applicable pharmacopoeia and regulatory requirements.

Pharmacopoeia Compliance: Putting It All Together; What Is on the Horizon

The final article of the series (12) attempts to summarize and pull all the various threads of the individual articles together into one consolidated picture of pharmacopoeia compliance. A holistic view is provided for the roles, responsibilities, activities, and other considerations, which are necessary to ensure compliance across the bio/pharmaceutical industry. The article continues with a look ahead at topics that will likely result in further evolution in the pharmacopoeias around the world. Some of the future trends explored are: new approaches to specifications, including those for complex biotherapeutics; the use of analytical quality by design and continuous manufacturing; concerns with impurities, such as N-Nitrosamine contamination; and the growing importance of national pharmacopoeias from around the world, for example those in China, Russia, and Brazil. This look into what is on the horizon can help companies prepare for the inevitable changes in the pharmacopoeias and ensure the continued supply of quality medicines to patients globally.

The need for pharmacopoeia compliance and the challenge of achieving it are explored in detail throughout the series of articles, which are intended to bring greater visibility and understanding of this fundamental principle to the bio/pharmaceutical industry. The articles present many facets of the processes, people, and tools necessary for a company to comply with the pharmacopoeia as well as their approved drug product registrations. The articles reflect the continuing evolution of the pharmacopoeias, their requirements, and the need for harmonization to achieve truly global standards.

Along with the understanding and assistance provided to those who perform the work, the articles have the additional goal of helping to ensure the continued availability of medicines with consistent quality. Meeting the necessary compliance requirements for these medicines ensures meeting the needs of patients around the world, regardless of where the patients live, where the medicines are manufactured, or which pharmacopoeias may apply.

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.

Pharmaceutical Technology Regulatory Sourcebook eBook

Why Pharmacopoeia Compliance Is Difficult,

Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions,

,” Pharmaceutical Technology Regulatory Sourcebook eBook, 14–23 (March 2020).

A Practical Approach to Pharmacopoeia Complianc

J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions LLC. Joseph A. Albanese is the director of Analytical Strategy and Compliance at Janssen Research and Development, LLC.


Vol. 44, No. 9
September 2020
Pages: 60­-64

When referring to this article, please cite it as J.M. Wiggins and J.A. Albanese, “Pharmacopoeia Compliance:A Practical Guide,” 

Articles

Processes, people, and tools are needed to comply with the pharmacopoeia and approved drug product registrations.

Pharmacopoeia Compliance:  A Practical Guide

A previous article in this series focused on the questions of why and when a company would submit a monograph to the pharmacopoeias (1). This article details the more operational aspects of monograph submissions, answering the question of how to participate. This question, in turn, is best approached by considering the following: who in the company is responsible for monograph submission and follow-up; what information and materials are needed to enable the elaboration process; and which pharmacopoeias the company will interact with for monograph elaboration. These questions also help when considering how to approach the development of monographs that are harmonized across multiple pharmacopoeias.

	Consideration of which groups should have responsibility to submit the monograph

	After a company decides on its approach to monograph elaboration (i.e., if it will participate-the why and when) (1), the company needs to define who is responsible for preparing the documents for submission to the compendial authorities, as well as providing responses to questions received from the pharmacopoeia during the elaboration process. The company must take many factors into consideration when deciding which functional group will be responsible for this activity.

	Monograph elaboration responsibilities could fall to many different groups in a company. The responsible group must have the breadth and experience to work externally with the pharmacopoeias, as well as internally across several functional areas and have a clear understanding of post-approval regulatory and quality changes that a new or revised monograph may cause. The compendial affairs group may seem the most logical choice to have the responsibility because they should have well-established connections to the pharmacopoeias, already understand the pharmacopoeia processes, and have connections to the scientific liaisons that drive the monograph elaboration process. The compendial affairs group should also have a network of contacts already established in many functional areas across the company due to the nature and impact of their pharmacopoeia surveillance activities (2). There are other departments, however, that could be considered to have the responsibility for monograph submission, including the chemistry, manufacturing, and controls (CMC)/regulatory affairs group, because they are responsible for submissions to health authorities that would be impacted by the creation of a new monograph. This group also has the breadth to interact with many functions in a company. The responsibility could fall to the analytical development function or a quality group within a company since much of the information needed is typically owned by one of these groups and they may be most familiar with current methods and specifications for the drug substances or drug products.

	Understanding the pharmacopoeia monograph elaboration process should be considered when choosing a responsible function within a company. Each pharmacopoeia has its own requirements for monograph submission and the preferred timing when a company should submit a monograph. The function will need to define a strategy for monograph submission centered around timing and global harmonization, if desired. Not all functional areas have the proper global focus to ensure these are considered in the overall strategy to ensure the best outcome for a company entering this process.

	The monograph elaboration process can take several years to be completed. Therefore, project management and communication skills are important for the responsible function. The chosen group needs to know the current status of the project and be able to deftly handle questions that will inevitably come from the compendial authority. It must ensure a prompt turnaround time for obtaining answers from any affected department, so the monograph elaboration process is not delayed. The responsible department must ensure adequate resources are available for each affected department to fulfill the requests for additional information when they arrive. A connection to the tracking tools available to the compendial affairs group detailed, previously in this series (2), would be important for the chosen function given the lengthy process for monograph elaboration. Attention should be given to the complexity that exists within the industry as a result of joint ventures, collaborative business partnerships, and agreements. Appropriate consideration is needed for engagement across these functions and business(es) in establishing who has responsibility for the development of compendial monographs.

	The data needed for monograph development are owned by many departments within a company. Choosing a specific business function that owns or has technical oversight for the product development data could be a possibility to take ownership of the submission process. 

summarizes the various departments and their role in monograph elaboration. The functional area that owns the elaboration process must be able to address questions outside its own area of expertise, interacting with other functional areas to ensure the company is speaking with one voice. The submitter of the information for monograph elaboration needs to act as a single point of contact (SPOC) for all questions that will come from the pharmacopoeia scientists. This means that if an analytical group is chosen to be responsible for the monograph submission, they need to collaborate with other groups such as microbiology, quality, and regulatory when questions are received. Product knowledge and experience with the drug substance or drug product are also important considerations for the selection. The monograph submission is expected to include reports from the entire lifecycle of the drug substance and drug product from early development that resulted in a specific control strategy for that material, through the current marketed product stability data, and everything in-between. The chosen group for the elaboration process should be closely connected to several stakeholders that provide input for the needed information to create a monograph, including approved limits for the country or region of the intended pharmacopoeia, as well as microbiological controls, storage and distribution requirements, shelf-life data for that region, all necessary method descriptions, validation reports, and justification of specifications. Understanding the breadth of responsibility to act as the SPOC will drive the choice for the company. This in turn will help the monograph elaboration process to run more smoothly because there should be better flow of information between the company and the compendial authority.

	Although there are many potential owners for this responsibility, in the authors’ experience the compendial affairs function is best suited to lead a cross-functional team required for monograph elaboration. One significant reason is the length of the elaboration process, with the pharmacopoeial focus that the compendial affairs function brings throughout this period of time. Given that many companies frequently change their organizational structure, the interactions with the pharmacopoeia could stop if the focus of a different group with monograph elaboration responsibility changes due to a company reorganization. If a company has chosen to proactively work with global pharmacopoeias to establish monographs, the responsibility to drive elaboration or revision is best placed with a function that operates well across the matrixed environment that exists in most companies.

	Consideration of which pharmacopoeias to partner with for monograph development

	A company needs to decide where they will submit the monograph, and this is determined by several factors. A pharmacopoeia may communicate their interest to the company to develop a monograph for a specific drug substance or product. Alternatively, the company may approach the pharmacopoeia proactively to indicate their interest in developing a monograph. As detailed in an earlier article (1), the preferred timing of the pharmacopoeia to develop the monograph or the specific considerations for a company regarding the particular drug substance or product will enter into the decision. For many products, the monograph will first be developed in the 

) due to their preferred timing for monograph elaboration, as well as the likelihood of earlier regulatory approvals achieved by a company in the United States and Europe. The geographical location of the company may also influence where the monograph is first submitted, but the global nature of the industry and the availability of channels for communication with the pharmacopoeias should minimize this being a significant factor.

	Both general and specific information is available for companies interested in learning more about 

 monograph submissions. Monographs in the 

 are developed by the scientific staff and appropriate expert committees (3, 4). Monographs in the 

 are elaborated by the European Directorate for the Quality of Medicines and HealthCare (EDQM) staff and experts using two processes. The difference between the two processes is the number of manufacturers involved during the initial elaboration of a monograph. This is an important difference for companies to understand. One process-actually the fourth approach established for 

 monograph elaboration-is called P4, in which a single company, typically the innovator company before patent expiration, initiates the collaboration with EDQM to establish a monograph for a drug substance or drug product (5). With the P4 process, the innovator provides their methods and specifications for review and evaluation by EDQM. A draft monograph is published that will be applicable to all subsequent manufacturers once they receive approval from the European health authorities. The other process-the initial approach used to develop 

. monographs-is called P1, in which EDQM invites all currently approved manufacturers to participate in the monograph elaboration process (6). With the P1 process, the patent for the drug substance or product will have expired or will expire soon and generic-drug manufacturers have entered or will soon enter the market. The companies that choose to participate using the P1 process provide their methods and specifications, and the EDQM scientists develop and publish the draft 

 monograph that will be applicable to all current and future manufacturers of the drug substance or drug product. The differences between the two processes and their applicability are illustrated in 

	To assist companies who wish to participate in monograph development, the pharmacopoeia authorities have published documents to detail what information is required. EDQM has several technical guides (7) available to help the responsible function in a company gather the needed information for development of 

Technical Guide for the Elaboration of Monographs

 (8) provides useful information applicable to monographs for small-molecule drug substances, as well as excipients. EDQM has additional guides covering a wide range of monograph types, including finished products containing chemically defined active substances, synthetic peptides, recombinant DNA proteins, herbal drugs, and vaccines (7). The technical guides provide information that may be used for the P4 (single-company) or P1 (multi-company) monograph elaboration processes. 

similarly provides specific monograph submission guidelines covering chemical medicines, excipients, dietary supplements, and food ingredients (3). There is also information about 

 approach to biologics standards (9) and on their pending monograph process (10), which allows for development of monographs for articles awaiting approval by FDA. Supplementary Chapter III in the 

) provides their requirements for submission of monographs to the 

 (JP) posts instructions on their website related to monograph submission, including what information is required (11). For other national pharmacopoeias (e.g., those in China, Korea, India, Russia, and Brazil), the monograph elaboration process is less clear and typically occurs well after the 

	An important consideration when elaborating monographs with multiple pharmacopoeias is the concept of prospective or informal harmonization (1). The 

) guidance published by the World Health Organization (12) suggests that as new monographs are developed, harmonization of the requirements across the pharmacopoeias could be achieved. This approach to monograph development has been gaining acceptance across the pharmacopoeias for drug substances and products. This initiative has been undertaken through a collaboration between the bio/pharmaceutical industry and the pharmacopoeias (

) with visibility provided to other pharmacopoeias, including those in Japan, China, Korea, and India. The effort has resulted in the successful completion of several new, prospectively harmonized monographs for small-molecule drug substances and products. However, it is important to understand that monograph harmonization will not occur on its own, and specific commitment and actions are required of the company to achieve this goal. Separate questions may be received from each of the pharmacopoeias involved in the elaboration process, potentially increasing the effort for a company to develop the monograph. More material will be needed to establish the reference standards required by the multiple pharmacopoeias. The process of elaborating harmonized monographs may also be more challenging for the pharmacopoeias. If a company wishes to pursue monograph harmonization, it is critical to communicate this intent at the beginning of the process to each pharmacopoeia that will be involved. Timely, effective, and sustained communication with the pharmacopoeias is also required throughout the elaboration process.

	The desire to establish harmonized monographs may also meet with internal resistance in a given company, due in part to the potential impact on approved limits. Some tests based on general chapters that are already harmonized, such as uniformity of dosage units, are easily harmonized in a monograph. There are some limits, however, which cannot be easily harmonized based on what has been approved by different health authorities for a test. For example, the assay limits for a drug product may be 90.0–110.0% in the US and 95.0–105.0% in Europe. Impurity limits are usually the most difficult to harmonize. Although these limits should be safety-based, the regulatory review process sometimes drives impurity limits to be based instead on process capability. As a result, it is not uncommon to have differences between the acceptance criteria for impurities approved in different regions. Monograph harmonization could require a decision to tighten an impurity limit in a region, based on reevaluation of the company’s process and safety data to ensure the proposed limit makes sense to protect patients without putting undue burden on the manufacturer. It may be a challenge to convince impacted areas within a company that it is appropriate to tighten already approved limits solely to achieve harmonized monographs in the pharmacopoeias. The challenges of compliance with harmonized monographs that differ from approved product registrations will be detailed in another article in this series.

	Consideration of information and materials needed to support monograph development

	The responsible function in a company needs to clearly understand what information is required by a global or national pharmacopoeia for monograph elaboration or revision. As noted in the 

 guidance, “Pharmacopoeial standards are public standards that are science-based and data-driven and based on sound analytical measurement and accompanying validation data” (12). To achieve science-based monographs, existing specifications-the list of tests, references to analytical procedures, and appropriate acceptance criteria-that have been approved by the health authorities based on International Council for Harmonization (ICH) Q6A (small molecule) (13) and ICH Q6B (biotherapeutics) (14) guidance documents are an appropriate starting point. It may be a challenge to prepare monograph submissions for older products that may not have been developed under ICH guidance documents. A similar challenge is encountered when an existing monograph will be modernized by the pharmacopoeia. As discussed in another article (15), the health authorities’ expectations and pharmacopoeial requirements constantly evolve to remain consistent with current technology. This requires a manufacturer to complete a proper evaluation for older products to determine if it can meet the current regulations and guidance documents in order to develop a monograph for the drug substance or product, regardless of when the product was developed.

	The tests, methods, and acceptance criteria sent to the pharmacopoeia should align with the approved filing for the drug product, including information regarding the drug substance, in that country or region. However, not all tests in the approved filing may be appropriate for the monograph. Additionally, because the monograph submission typically occurs many years after first product approval, the documentation should include specifications that reflect all strengths and formulations for the drug product, even if some of these have only been recently developed and approved. The official monograph for that dosage form will apply to all strengths marketed, regardless of when the product was approved by the health authority. If the specifications provided for the monograph are different than what is filed for that country or region, a sound justification must be made since the pharmacopoeia will consult the health authority to verify the specifications are consistent with those approved. Specifications should also conform with the requirements in applicable general chapters for the specific dosage form included in the particular pharmacopoeia.

	The acceptance criteria set by the pharmacopoeias are typically based on shelf-life specifications that are approved by the health authority in that region. The 

 guideline indicates, “Specifications that limit market access by, for example, favoring one manufacturer to the exclusion of others should be avoided” (12). Stated another way, the pharmacopoeia standard should not override a health authority approval. The monograph acceptance criteria are meant to encompass all manufacturers of the material, including differences between synthetic schemes for drug substances or different formulations for drug products. It is a daunting task for the pharmacopoeia to achieve a sound scientific monograph that does not block a manufacturer.

	Once a company has selected the specific pharmacopoeia(s) and whether harmonization will be a goal, the company needs to provide a significant amount of data and documents to start the monograph elaboration process. The information sent to the compendial authority would include the following:

		Specifications, as defined by ICH Q6A (13) and Q6B (14):					

				A list of the tests proposed for inclusion in the monograph (

). These tests should be appropriate for the public standard and will be applicable to all manufacturers and materials covered by the monograph. Not all methods included in the product registration are necessary or appropriate for the monograph. No tests that are internal only should be submitted, such as particle size or bulk density, for a drug substance, or an assay for preservatives in a drug product.

				Analytical methods and associated validation reports used for release and stability/shelf-life testing.

				Microbiological purity methods and associated validation reports if they differ from compendial methods.

				Appropriate acceptance criteria, which should be stability/shelf-life limits since the monograph applies throughout shelf-life for the material or product. The limits should include registered limits only (i.e., no in-process or in-house limits for that market or region).

		Information about the drug substance, including chemical structure, molecular formula, formula weight, nomenclature (generic and International Union of Pure and Applied Chemistry [IUPAC] names), Chemical Abstracts Service (CAS) number, description, solubility, hydration, crystalline structure, and polymorphism. For complex biotherapeutics, this would also include the peptide map of the protein or peptide and its approximate formula weight.

		Information about each specified organic impurity and degradation product, including chemical structure and IUPAC nomenclature.

		Information about residual solvents and elemental impurities, which may be present in the material.

		Justification of specifications, as typically included in the product registration.

		Stability/shelf-life data report, typically covering the last four to five years of production.

		Certificates of analysis from three recent lots of drug substance and three lots of each strength of drug product. A batch overview from recently released lots may also be provided (typically, not less than 10 batches).

		Information related to storage and labeling requirements.

	Companies have different approaches to providing the monograph submission to the compendial authorities. Some companies will provide a draft monograph following the pharmacopoeia’s respective format and style, with proposed specifications for each test and method descriptions to communicate only enough details as needed in the monograph. Other companies will submit specifications, methods, and validation reports as they exist in quality and regulatory documents, with no redaction prior to providing them to the compendial authorities. It is suggested that a company define its approach to monograph submissions in a procedure or job aid given the volume and complexity of the information and materials needed to be provided to the pharmacopoeia.

	Regardless of the approach taken to submit information, the compendial scientists will thoroughly review all the documentation provided to prepare their own draft of the monograph. For the validation information, a good practice is to prepare a method validation summary for critical methods such as assay or chromatographic purity as this can result in fewer questions from the pharmacopoeia. This is especially true when there are different synthesis schemes used for a drug substance or multiple strengths for a product that were developed and validated at different times by the company.

	After the documentation has been initially reviewed by the compendial authorities, the company will be requested to provide physical materials to support the elaboration of the monograph, including samples of drug substance, drug product(s), and available impurities, all of which will be used for testing performed in the compendial authorities’ laboratories. It is extremely helpful to anticipate this request from the compendial authority, with the samples gathered by the company while the documents required for the submission are first being collected. For complex biotherapeutics, the in-house standard that is used in the company’s assay should be provided, as well as any other qualified materials that are used as controls in an assay.

	Reference standards must be provided for the active ingredient, any specified impurity for the drug substance, and any specified degradant for the drug product. The impurity standards are typically used to identify the impurity peaks observed and ensure system suitability in chromatographic procedures. If specified impurities are not available, a suitable “dirty” batch of the drug substance may be used as the reference standard, provided the individual impurities present can be satisfactorily identified. Each material should be provided in sufficient quantity to allow for testing and for the compendia to establish their reference standard for the material. Each material requires a certificate of analysis that will enable the pharmacopoeia scientists to qualify it as a reference standard that can be used by any company. The pharmacopoeia may also request a Safety Data Sheet (SDS) and other supporting data (e.g., infrared [IR] spectra, Raman spectra, nuclear magnetic resonance [NMR] spectra, mass spectra [MS], X-ray powder diffraction [XRD] spectra, differential scanning calorimetry [DSC], chromatograms, etc.) and a bovine spongiform encephalopathy/transmissible spongiform encephalopathies (BSE/TSE) statement for materials provided by the company. It is common for the pharmacopoeia to request additional quantities of reference standards that they can qualify and provide for other laboratories to use as suitable reference standards. The pharmacopoeia may request assurance from the company that sufficient amounts of material will be available to establish their second batch of compendial reference standard; this becomes a commitment from the company to support the continued use of the monograph once it has become official.

	Additionally, the compendial authority may ask for clarification of steps provided in a method or for additional shelf-life data amongst other questions from their first review. These may include robustness data using other instrument brands to perform the analysis, questioning or tightening system suitability criteria, and adapting gradient profiles for separations. The pharmacopoeia authorities prefer to have a single high-performance liquid chromatography (HPLC) analysis that can be used for drug substance, drug product, and associated impurities or degradants. If a content uniformity analysis is needed for the product, it is preferred that it is run with the same method as the assay.

	Each elaboration process is different and brings to light different questions and approaches for establishing the monograph. The following highlight different scenarios that have been encountered by the authors during monograph elaboration.

 It is the authors’ experience that impurity limits for drug substances and drug products have the most challenges. Monographs on pharmaceutical substances and products should take account of the principles defined in the ICH Q3A (16) and Q3B (17) guidelines and follow regulatory decision-making. However, there are also practical considerations that emerge in the transition of a company’s private standard into the public standard embodied in the monograph. For example, drug substance methods typically focus on identifying synthesis impurities and API degradants, whereas drug product methods only focus on degradants due to the formulation or API degradation. It can be challenging to ensure that a chromatographic procedure for a drug product can distinguish a degradation product from a synthesis impurity present in the drug substance. An inability to identify a particular impurity peak in a chromatogram may lead to it being an unspecified impurity in the monograph, even if it is listed as a specified impurity in approved product registrations. If there are requirements needed for purity, especially in the case of significant degradation, this information must be shared with the pharmacopoeia authority.

Tests that are dependent on route of synthesis.

 There are some tests where the method or acceptance criteria are tied to a specific material, making it difficult to establish the monograph. To address this situation, the 

 monograph may include modifications to what is filed in Europe, in order to make the monograph applicable to all materials and manufacturers. The 

, on the other hand, has introduced the flexible monograph (18) approach for drug substances that use different synthetic routes, when a “one-method-fits-all” approach cannot be easily achieved. For drug substances, the impurity profile can be completely different depending on starting materials, solvents, and catalysts used upstream in the synthesis route. One method may not be able to capture all synthesis impurities so the 

 flexible monograph allows for additional methods for assay and chromatographic purity for these materials.

Tests that are dependent on product formulation. 

Dissolution testing for solid oral dosage forms presents a challenge for the pharmacopoeia monograph. Differences in formulations often result in different release profiles when a specific dissolution medium and sampling time point(s) are described. The 

 flexible monograph approach allows for more than one dissolution test to be included in the monograph. This may also be true for other tests in the monograph. For the dissolution example, manufacturers provide their dissolution method and acceptance criteria that are specific to their formulation to 

 since the initial method published may not be suitable for that company’s formulation. By including the formulation specific test as “Test 2”, the 

 provides flexibility for the manufacturer to select the appropriate test to be used. However, there are some products where the flexible approach seems to be carried to an extreme: the 

 monograph for Diltiazem HCl Extended Release capsules contains more than 15 different dissolution test options. With these options, it is the responsibility of the manufacturer to ensure their drug product labeling reflects which test is used, if it is not Test 1. If there is no designation in the labeling, it is assumed the product uses Test 1 listed in the monograph. Other pharmacopoeias are considering different approaches to dissolution testing in monographs, which will be explored in a later paper in this series.

	Monographs for complex biotherapeutic products

	As mentioned earlier, the ICH Q6B guideline (14) for biological/biotechnological products (BTP) is a good starting point for a company elaborating a BTP monograph with the pharmacopoeia. However, the concept of product specific monographs for complex BTPs, such as monoclonal antibodies (mAbs), is still subject to vigorous debate between health authorities, pharmacopoeias, and industry. The biggest challenge is the ability to fully characterize a complex biologic material with the available analytical technologies. Given differences in the manufacturing processes and limitations in analytical capabilities, exact copies of complex BTPs cannot be produced, only biosimilars can be manufactured. This is unlike small-molecule drug substances and drug products where full characterization is expected and can be readily achieved.

	As a result, there are only a few monographs for complex BTPs with multiple manufacturers published in the 

) for an orphan drug (single manufacturer). As of this writing, the other global and national pharmacopoeias, including 

, have not published any monographs for BTPs; indeed, the 

 are exploring alternate approaches to product-specific monographs for establishing pharmacopoeia standards for BTPs. With the limited availability of monographs at this time, the approach to harmonization of BTP monographs is limited for these types of products. The EDQM has published a technical guidance document for 

	Consideration for specific tests to be performed on complex biotherapeutics are outlined in the general monographs located in the pharmacopoeias, including 

). All pharmacopoeias have been publishing general chapters for the tests employed for BTP analysis and more chapters are currently being elaborated. General chapter elaboration for BTP products offers one of the best opportunities for prospective harmonization across the pharmacopoeias today.

	Tests to consider for inclusion in a BTP monograph are listed in 

. These include identification of product-related impurities resulting from oxidation or deamidation or mechanisms that cause aggregates to form. The impurities are measured by a wide range of analytical technologies, so it is important that specific methods are provided to the pharmacopoeia authorities. Additionally, there is significant attention given to process-related impurities that can adversely impact a patient if present. Testing is required for bacterial endotoxins, host cell proteins, and host cell DNA. Risks from impurities related to viruses and prions must also be considered if using cell culture or media supplemented with components of animal or human origin. Many of these more common tests are typically covered by existing general chapters in the pharmacopoeia.

	Setting strict acceptance criteria for tests in a monograph for complex biologicals (e.g., mAbs) can be extremely difficult. As noted earlier, generic mAbs are “similar” and not an exact copy, as is the case for small-molecule entities. Given that each product is “similar” and uses a unique control strategy, a single set of acceptance criteria would be inappropriate to list in a monograph for many of the tests. If specific ranges were published, the approach would not be capturing the entire class of “similar” materials and could essentially block manufacturers from the market. This would be contrary to the approach advocated in the GPhPs that monograph “specifications that limit market access … should be avoided” (12).

	The flexibility introduced by the general chapters in the pharmacopoeias also creates some complexity when trying to find a method that is suitable for all complex biotherapeutics covered by a product-specific monograph. The 

 general monograph 2031 for monoclonal antibodies allows for many techniques to analyze a required attribute of a BTP. An example of this is given in 

 for the Charged Variants test in the infliximab concentrated solution monograph that became official in January 2019. Two companies’ specifications are shown for the test. It would be impossible to decide which of these techniques is best suited for the analysis, and there is no way to compare the acceptance criteria established for each technique to demonstrate they provide “comparable” results. This is not like comparing the use of different columns for a reverse-phase C18-based HPLC method typically used for small-molecule drug substances and drug products.

	EDQM recognized this difference and placed these types of tests, which are variable based on allowable techniques and results generated, in the “production” section (20) of their 

 monograph. The “production” section of the monograph constitutes mandatory requirements for a manufacturer, including in-process testing or tests to be performed on the final drug product. EDQM also introduced the approach where an example method (19) is provided in the monograph, but a manufacturer may instead use their own method, subject to approval by the competent health authority. This approach allows the requirement to be present in the monograph but gives a manufacturer flexibility in meeting it. This flexible approach also ensures that no manufacturer will be blocked from the market.

	Additionally, for BTP methods, there is little robustness information being generated by manufacturers across instruments from different vendors. Most companies tend to pick a platform technology and then employ it across the organization allowing for smoother method transfers and decreased method variability. This makes the monograph elaboration process more complicated because manufacturers, pharmacopoeia scientists, and government testing laboratories will most certainly not standardize on a single vendor’s instrument.

	The understanding of what is required for BTP monographs has been under discussion between industry and the pharmacopoeia for many years. Industry’s concern was recognized by EDQM and is evident in the flexible approach used to complete the first 

 monographs for monoclonal antibodies with multiple manufacturers. It remains to be seen if other pharmacopoeias will follow this approach or not. This is new territory for the pharmacopoeia authorities since this is the beginning of monograph elaboration for these types of therapeutic entities. As analytical capabilities are enhanced and technology advances, the required tests and appropriate techniques to analyze mAbs will evolve and so will the future requirements in the pharmacopoeias. There are sure to be other hurdles to overcome as industry, health authorities, and pharmacopoeia authorities gain more experience with complex BTP monographs.

	Consideration of specific tests to be included in monographs for vaccines for human or veterinary use are outlined in the 

 chapter <1235>. There are also specific technical guides from the EDQM regarding human and veterinary vaccine monographs (21, 22). Vaccine monographs in the 

 often contain a “production” section, as was described for other complex biotherapeutic products. Like other drug types, there are general chapters available to describe tests and what should be considered to execute the methods appropriately. Tests to be considered for inclusion in monographs for vaccines are listed in 

	Excipient monographs are elaborated or revised in a similar fashion as drug substance and drug product monographs. Typically, an excipient manufacturer will drive the elaboration process with the specific pharmacopoeia. In 

excipient monographs, the control of additional properties (e.g., functionality-related characteristics) may be included. The draft monograph will be available for commenting, and a drug product manufacturer will have to comply with the monograph when published as official. Other than performing surveillance and providing comments on proposals, there is not much for a bio/pharmaceutical manufacturer to do for this type of monograph.

	General chapters are created or revised in a similar fashion as drug substance and drug product monographs, except it is usually the pharmacopoeia that drives the process. Elaboration of a new chapter is driven by regulatory changes (e.g., implementation of ICH Q3D) or new analysis techniques that become more routinely used by industry (e.g., methods for biotherapeutics analysis mentioned above). Typically, the pharmacopoeia will establish a working group including stakeholders from industry, academia, and regulatory agencies for the elaboration of a specific new chapter. This is another great opportunity for a company to participate with the pharmacopoeia to influence the outcome of the chapter. The draft general chapter will be available for commenting and bio/pharmaceutical manufacturers will have to comply with the chapter (unless it is informational) when published as official.

	Pharmacopoeia monographs are science-based public standards that are data-driven and built on sound, validated analytical measurement or microbiological practices. If a company decides to participate in the elaboration process, having clear responsibilities to ensure the elaboration process is followed and driven to completion is necessary if the outcome is to be appropriate for the company. Regardless of which type of monograph, a company must recognize that the elaboration process is essentially taking private standards for each manufacturer and making it a single public standard for all companies to follow, so some flexibility is needed. Additionally, being proactive and having a strong collaborative relationship with the pharmacopoeia scientists enables a company to more effectively advocate for changes in the proposed monograph should conflicts arise. The same advocacy approach also applies to the elaboration or revision process for general chapters. The next article in this series will illustrate how pharmacopoeia compliance can be a challenge even when a company participates proactively, since the monograph may differ from product registrations.

	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.

	1. J.M. Wiggins and J.A. Albanese, “Monograph Development: Why and When to Participate,” 

	2. J.M. Wiggins and J.A. Albanese, “Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions,” 

	4. USP, “USP Guideline for Submitting Requests for Revision to 

: General Information for All Submissions,” 

	5. EDQM, “Elaborate a Monograph–Procedure 4”, 

	6. EDQM, “Elaborate or Revise a Monograph–Procedure 1”, 

 Technical Guide for the Elaboration of Monographs

“USP’s Commitment to Stakeholder Engagement Related to Biologics Licensed under the Public Health Service Act (PHSA),” 

 18th Revision of Japanese Pharmacopoeia–Guideline for Creating a Draft

 (Office of Standards and Guidelines Development, Pharmaceuticals and Medical Devices Agency, January 2017).

This article details the more operational aspects of monograph submissions, answering the question of how to participate.

Throughout this series of articles, it has been emphasized that the bio/pharmaceutical industry must comply with requirements published by pharmacopoeias around the world. Several considerations have been presented to illustrate that pharmacopoeia compliance can be difficult. A previous article (1) highlighted compliance challenges resulting from the elaboration of monographs for drug substances and products. These challenges can be considered externally-based, driven by decisions made by the pharmacopoeias during the monograph development process. There are other compliance challenges that are internally-based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. One such example can be found with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment, ensuring compliance with applicable compendial and regulatory requirements. This case study is based on the experience of one of the authors (2) but is applicable to all companies across the broader industry, illustrating the potentially surprising point that some compliance difficulties may be of the company’s own making.

	During early development in the product lifecycle (3), various raw materials are used to prepare the drug substance, with the goal of consistently providing this active pharmaceutical ingredient (API) with appropriate quality and purity. Many of the raw materials are completely consumed during the manufacturing process, serving as building blocks that are converted into intermediate materials prior to the ultimate drug substance. Other materials may not be completely consumed, carrying over into the drug substance or drug product as residual materials or impurities. These residual materials may be an especially important consideration for complex biotherapeutic products (BTP). Continuing in the product lifecycle, the subsequent development of the dosage form involves the addition of excipients to the drug substance, with the goal of providing safe and effective delivery of the API in the drug product to achieve the intended therapeutic outcome. Appropriate product development information, along with safety, clinical, stability, and other data, are provided to regulatory agencies around the world to gain marketing approval for the drug product.

	This article focuses on the raw materials and excipients used in the manufacture of drug substances and drug products. A company must comply with their approved product registrations and with appropriate compendial requirements, according to the expectations of regulatory agencies (3). The pharmacopoeias also provide information about the need for compendial compliance. For example, the General Notices in the 

) indicate that drug substances and excipients must comply with all the requirements stated in the applicable monograph (4). The General Notices in the 

United States Pharmacopeia-National Formulary 

) state, “Official products are prepared … from ingredients that meet 

 standards, where standards for such ingredients exist” (5). Clearly, APIs and excipients used to manufacture the drug product must meet compendial requirements. The 

 General Notices continue, stating that the drug substances and excipients are themselves prepared “from ingredients complying with specifications designed to ensure that the resultant substances meet the requirements of the compendial monographs.” Again, the active ingredients and excipients clearly must meet the monograph requirements. Information is lacking, however, as to the ingredients used to prepare the drug substances and excipients. In particular, what are the appropriate specifications for the raw materials that will ensure compendial compliance for the resultant APIs and excipients?

	This lack of clarity about the control of the raw materials may lead to compliance challenges. The drug development/approval process takes many years and involves a large number of wide-ranging functional areas across the entire company, including research and development, procurement, supply, quality, and regulatory. It is essential for these groups to remain connected and aligned throughout the entire process, with sustained communication and appropriate documentation, to deliver an effective and efficient outcome for the company overall. It can be especially important for decisions made early in the development process to be communicated and understood across all departments. Equally important, the responsible groups making early decisions should have visibility, or line-of-sight, to the strategy and expectations of other groups involved later in the product lifecycle, as part of an end-to-end approach to the overall process (6). The situation is made even more complex as more bio/pharmaceutical companies outsource the production of drug substances, and contract manufacturers work with many customers having different material requirements.

	There are important and fundamental questions about the materials used in product development and manufacturing that need to be considered throughout the product lifecycle. How does a company ensure the suitability and compliance of the raw materials and excipients used to support a broad product portfolio in a global environment? Are acceptable materials being used? Is appropriate testing being performed? How is this information communicated internally, across impacted functional areas? How is the information communicated externally, to external partners and suppliers, as needed? How is the information communicated externally to regulatory agencies around the world? These important questions can be expressed in simpler terms, as follows:

	These questions relate to the selection, sourcing, testing, and filing for excipients and raw materials, and the interplay among them is shown in 

. Each area is connected to, and impacts, the others, but one key aspect is the potential disconnect that can occur between what is sourced and what is filed for these materials. A consistent, cross-functional approach is necessary for a company to answer the questions in a way that ensures compliance with appropriate regulatory, compendial, functional, and quality requirements. Without a consistent approach that is understood and followed across the entire company, compliance problems can emerge.

	The level of understanding about the materials used to prepare drug substances and drug products increases as a company moves through the product lifecycle (

). Beginning in early development, the focus is on ensuring the materials are “fit for purpose”, with appropriate functionality of the materials (“what do you need?”) to support their intended use in the drug substance or product. At this stage, there are also questions about possible sourcing of the materials (“what do you buy?”) and appropriate quality (“what do you test?”). As development continues toward product registration, launch, and supply, the functionality of the material is better understood, and quality and compliance considerations now become most important. The situation is increasingly complicated in today’s global industry, with additional regulatory expectations arising in important markets. Appropriate sourcing and testing are still key considerations (“what do you buy?” and “what do you test?”) that bridge product development to supply, but a critical focus now surrounds the specific details that will be included in the product registration (“what do you file?”).

	The differences that emerge in this case study are internal to the company, based on misalignment of expectations and requirements for raw materials and excipients between different functional areas. Without a line-of-sight or end-to-end perspective across the product lifecycle, different areas will likely have different understanding and definitions for the materials used during development, continuing into product launch and supply. Although a definition is provided in the International Council for Harmonization (ICH) Q6 guidelines for an excipient used in a drug product, there is no information about the ingredients that are used in the preparation of the drug substance (7). To enable a consistent process for the selection, sourcing, testing, and filing of excipients and raw materials, it is critical to have clear, practical, and specific definitions, not just for the materials themselves, but also for the grades that may be available. The definitions used for materials throughout this article are listed in 

		Raw materials are used in the manufacture of the drug substance and should not be present in the final drug product.

		Residual materials may be used during the manufacture of the drug substance or drug product, but may not be completely removed, and as a result may still be present in the finished product.

		Excipients are ingredients added to the drug substance during manufacture of the drug product and intended to be present in the final product.

	While these terms and definitions may differ between different companies, the important point is to have the discussion and reach a common understanding within a company to establish a consistent, cross-functional approach to compliance.

	The definitions for materials are based on their use in the manufacture of the drug substance and drug product. The definitions for material grades are based on the materials that are purchased and the testing performed on them. The definitions for grades used in this article are listed in 

 and include compendial grade, multi-compendial grade, supply grade, and reagent grade. Compendial and multi-compendial grade relate to the availability of one or more monographs for the material in the pharmacopoeias. Supply grade is a term used when there is a need for a company to have visibility to the supply chain and change control for the material. As an example, for a material purchased from a distributor, a company may need to be notified if the distributor changes their supplier of the material, as this could have an impact on the drug product manufacture. Similarly, for a material purchased directly from a manufacturer, a company may need to be notified if changes are made to the manufacturing process of the material as this may also impact the manufacture and quality of the drug product. The notification from distributors and manufacturers can be very important for control of the materials used in the highly-regulated bio/pharmaceutical industry. Finally, reagent grade applies to materials not covered by the criteria above. The use of reagent grade materials should be carefully considered to ensure their acceptability in the manufacture of a drug substance or product, from a quality and regulatory perspective.

	It is now possible to look at the four questions posed earlier in greater detail, with the common understanding provided by the definitions for materials and grades given above. The underlying questions will enable discussion and drive decisions that are consistent across the various functional areas. Many of the underlying questions are the same  but are examined from different perspectives by different functional areas. The goal is to align on the approach used throughout the product lifecycle for the selection, sourcing, testing, and filing of the materials.

 The question, “what do you need?”, arises at the very beginning of development, and the answer depends on how the material will be used. Is it an excipient used in the drug product, or is it a raw material used in the drug substance? This is a fundamental question that should be easy to answer.

	If the material is intended as an excipient, its safety must be confirmed. Is safety or toxicology data available in the literature? Does the material have generally recognized as safe (GRAS) status? Is it listed in the FDA Inactive Ingredient Database showing the maximum level that has been approved in drug products for a particular route of administration or dosage form? When looking at the functionality of the material, it is important to identify the unique characteristics that contribute to its suitability for the intended use. What specific materials and grades should be considered? Will the material support a quality-by-design approach to manufacturing? Is viscosity or particle size important? Are there impurities that can impact the overall quality of the material itself or the quality of the product that will be made from it? Are there residual solvents or elemental impurities present? Depending on its use, is there a need to consider microbiological quality or sterility?

	The functional and quality requirements for the materials determined during development are important to other groups involved later in the product lifecycle. These requirements will be tested by the quality groups to ensure the identity, purity, and performance of the materials. The requirements may eventually be listed and justified in product registrations, with potential impact on post-approval change control. At a certain point, questions arise as to the availability of the material. These sourcing considerations are not necessarily fundamental during early development but are critical in late development and commercialization.

 The question, “what do you buy?”, builds on the decisions made in new product development and evolves throughout the product lifecycle. Again, you start with the question of how it is used because that, in many ways, determines what you buy. The development scientist may pull a raw material or excipient off the laboratory shelf to start their work. The material may have been purchased through a chemical catalog or it could be a promotional sample from a potential supplier. The scientist might check what is available in the chemical stock or manufacturing area that can be used in development studies.

	There is still a need to understand the critical quality attributes (CQAs) for the material to enable discussion with potential suppliers. At this stage, there is a focus on what is available. Is there only one supplier or are there multiple sources that can provide the material? Is visibility to the supply chain or change control necessary and possible for the material?

	As product development proceeds, considerations of the cost and available quantities become important. If there are multiple sources for the material, what is the basis for choosing one supplier over others? Is there a need to qualify more than one supplier in case of material shortages? What experiments are needed to ensure suitability of materials from different suppliers for use in the specific formulation? Have the suppliers been previously audited by the company? Were the audit findings acceptable? Are specific materials with different characteristics available (e.g., hydroxypropyl cellulose with different molecular weight and viscosity properties) and is one better suited for the intended function? All of these questions lead to the ultimate determination of the materials and suppliers that will be used in the manufacture of the drug substance and product. These decisions also impact the testing performed and provide information about what may be filed in product registrations. Typically, the purchased materials should be compendial, multi-compendial, or supply grade. In some cases, reagent grade materials may be considered, although the ability to use reagent grade materials in drug product manufacture is fairly limited due to quality and regulatory concerns, in the authors’ experience.

 The question, “what do you test?”, depends again on how the material is used. If the material is used as an excipient and there are applicable monographs, the quality groups need to ask whether they will perform all tests in one or more pharmacopoeias. In which countries will the product be filed? This determines which pharmacopoeias may be applicable when ensuring compendial or multi-compendial compliance. What if the material is used as an excipient but is non-compendial, meaning there is no monograph for the material in the pharmacopoeia?

	Understanding CQAs for the intended use is again important so that quality testing can be performed to control these characteristics in releasing the material. What tests are performed by the supplier? What are the supplier’s acceptance criteria? One key point in going through the exercise at this stage is that there must be discussion and agreement with the supplier for any additional tests or different limits that will be required based on the use of the material. A company making these decisions in a vacuum or without interaction with the supplier can put the availability of the material at risk and create potential challenges for the company. Release tests should include analytical and microbiological controls to evaluate overall quality, ensuring the identity, purity, and functional suitability of the material. Control of specified impurities is a key consideration. Some tests for the functionality-related characteristics of the material may be performed as “internal tests” and not included in the product registration. These internal tests are performed for release of the material but do not represent a regulatory commitment. This leads to the final question to be considered.

The question, “what do you file?”, also depends on how the material is used because this determines what may be listed in the product registration. One key lesson is that the answers to the prior questions (“what do you need, buy, test?”) do not necessarily have to correlate with what you file. What is listed in the registration does not have to match what is sourced or even tested. This returns to the potential disconnect that was presented earlier in 

	At a practical level, how the material is used determines which section of the Common Technical Document (CTD) will contain the information about the material that is provided to regulatory agencies. Recall that the bio/pharmaceutical company must comply with approved product registrations, including applicable compendial requirements. What is listed in the registration becomes a regulatory commitment. Based on how the material is used, does the company need to commit to compendial testing in the registration per the applicable monograph? If used as an excipient, the answer is “yes.” For which pharmacopoeias is the company claiming compliance? It is recommended that compliance with only one pharmacopoeia be listed in any product registration, according to which particular pharmacopoeia is applicable for the specific country to meet regulatory expectations in the filing. This idea will be further detailed in the following strategy section. Are there additional tests, such as quality attributes and functionality testing, that are critical to product manufacture and should be included in the registration?

	In determining what to list in the product registration, a company must choose wisely because the decision essentially locks you in. Considering what may be an extreme example, imagine an ingredient used as a “raw material” as defined in this article, and that it is an important component in the preparation of the drug substance. Imagine further that the company wishes to control the particle size of this material, not as a CQA, but to aid in processability during manufacture of the active ingredient. In this example, because it is an important component in the manufacturing process, visibility is needed for the supply chain and change control of the raw material. This situation is consistent with the use of “supply grade” material.

	Imagine, however, that the supplier will only assure supply chain visibility if the company purchases “compendial grade” material. It must be stressed that procuring compendial grade material does not mean that compendial compliance must be listed in the registration; nor would particle size testing necessarily need to be included. Perhaps the company has determined that only assurance of the identity of the material is required for quality testing and in the registration to support the material’s intended use in manufacturing. The particle size might be an additional internal test for control, while the company gains more experience with the manufacturing process. If, however, there are disconnects between the different functional groups in the company and in their decisions, it is conceivable that the registration might list compendial compliance (based on the material procured) and the particle size test (based on the testing performed) because a consistent approach was not followed.

	The result is an unnecessary regulatory commitment with which the company must now comply. This situation can create challenges for many groups, including quality (“why do we now have to perform testing per the compendial monograph?”), manufacturing (“after scale-up, we no longer need to control particle size for the material”), and procurement (“we would like to change to a lower-cost supplier who provides supply chain visibility for the material without reference to the monograph”). Any changes to address these challenges will require that the company make updates to the product registrations, with the associated difficulties typical of the change control process. This situation illustrates the intersection of the four questions considered and enables discussion of principles and strategies that can help avoid the potential challenges.

	The goal is for a company to establish a consistent, cross-functional approach for the selection, sourcing, testing, and filing of materials used to manufacture drug substances and products, in compliance with applicable compendial and regulatory requirements. Consistent principles and strategies should be established that will be followed throughout the product lifecycle by all functional areas in the company. Using the definitions provided earlier, the following principles are proposed:

				An excipient should be compendial grade, unless a monograph for that material is not available in the pharmacopoeia.

				If there is more than one applicable monograph in the multiple pharmacopoeias, the material may be multi-compendial grade.

				An excipient without a compendial monograph should be supply grade.

				A raw material should be supply grade.

				Even if there is a monograph in the pharmacopoeia for the material, its use as a raw material does not require sourcing, testing, or filing as compendial grade.

				A raw material may be procured as compendial grade (to have supply-chain and change control visibility), but the filing should only include the minimum requirements to ensure the quality and suitability of the material. The filing should not reference the compendial monograph.

				A residual material may not be applicable in all small-molecule or complex biotherapeutic processes. Whether the material needs to be compendial grade or supply grade should be addressed on a case by case basis.

				The strategy for a residual material would generally align with the raw material strategy.

				Testing and filing should reflect appropriate, minimum requirements for the material.

	As stressed before, in establishing the principles within a company, it is important to have the discussion with colleagues from all functional areas involved throughout the drug product lifecycle to develop a consistent approach for the appropriate selection, sourcing, testing, and filing for the materials used.

	Strategies for excipients: compendial vs. multi-compendial

	The principles given above enable a company to establish their strategy based on the fundamental use of the material as an excipient or raw material. 

shows an appropriate strategy for the case where the selection process determines an ingredient will be used as an excipient. The other functional area decisions for sourcing, testing, and filing are shown in the three columns, with the corresponding choices for material grade shown in the colored boxes. Assuming there is an applicable monograph in one or more pharmacopoeia, the sourcing decision for an excipient is either compendial or multi-compendial. The testing decision is also compendial or multi-compendial. The filing decision is compendial, with the recommendation that only one pharmacopoeia is referenced for the material in any registration. The decisions in this strategy can be better understood by looking more closely at specific situations.

	It is instructive to look at the interplay of the decisions for sourcing and testing when considering whether compendial or multi-compendial grade is the better choice for an excipient used in a particular drug product. It will cost more for a company to purchase an excipient sold as multi-compendial grade because the supplier of the material must perform additional testing to ensure compliance with more than one monograph. The user of the excipient may be able to leverage the multi-compendial testing performed by the supplier to reduce their own testing of the material, by accepting some results from a qualified supplier’s certificate of analysis (COA). This can be done provided the user of the excipient performs at least one specific test to verify the identity of the material. Additionally, the user must establish “…the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals”, as stipulated in the US 

	Alternatively, the excipient user can perform all testing needed to ensure multi-compendial compliance for the material. This can be accomplished even if the material is purchased to comply with the monograph in only a single pharmacopoeia. This approach is not “testing into compliance”. To be considered compendial grade, a material must be prepared according to recognized principles of good manufacturing practice (GMP) and meet the requirements in the pharmacopoeia monograph, as noted in the 

The authors present a case study with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment, ensuring compliance with applicable compendial and regulatory requirements. 

Author | Joseph A. Albanese