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16.1 Drug substance physical and chemical properties The major “modules” or parts of the New Drug Application (NDA) that concern the Chemical Development team are those covering the “drug substance.” These modules are part of a larger collection of information referred to as the Common Technical Document (CTD) and are generally organized using the International Council on Harmonisation (ICH) prescribed format. Within the “drug substance” module of the CTD, there are a number of major parts and subparts that describe all elements of the chemical process, analytical methods, characterization of all relevant materials including impurities, and requirements of the cleaning processes. The complete list of required sections is presented in Table 16.1. Key point Within the “drug substance” module of the CTD, there are a number of major parts and subparts that describe all elements of the chemical process, analytical methods, characterization of all relevant materials including impurities, and requirements of the cleaning processes.
The tasks that the Chemical Development team must execute are described in this section of the book and are roughly organized following the list of current requirements suggested by the ICH guidelines for a CTD as summarized in their guidance document “M4Q.” Guidance M4Q provides the framework for assembly of regulatory documents in a format that permits effective review by both US and international agencies of the application for approval to market the drug. These modules of a CTD cover nomenclature, chemical structure, and physicochemical properties of the drug substance as well as synthetic and analytical methodology. One is required to provide the International Union of Pure and Applied Chemistry (IUPAC) chemical name of the drug substance and the US Adopted Name (USAN) as well as any common names for the material. A standard graphical representation of the structure is presented along with general physicochemical information about the material. The properties described should include spectroscopic properties, for example the ultraviolet-visible (UV-Vis) spectrum, melting or degradation range, and solubility properties. The rotation for optically active substances should be provided as well as acid–base properties, as pKas, if appropriate. The names and addresses of the manufacturer(s) of the drug substance and all subcontractors involved in the work should be provided. Approval to manufacture a given Managing the Drug Discovery Process. http://dx.doi.org/10.1016/B978-0-08-100625-2.00016-7 © 2017 Elsevier Ltd. All rights reserved.
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Table of contents for sections of a CTD relevant to chemical development Table 16.1
The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality—M4Q(R1) Quality Overall Summary of Module 2, Module 3: Quality 2.3 Quality Overall Summary (QOS) 2.3.S Drug Substance (name, manufacturer) 2.3.S.1 General information (name, manufacturer) 2.3.S.2 Manufacture (name, manufacturer) 2.3.S.3 Characterization (name, manufacturer) 2.3.S.4 Control of drug substance (name, manufacturer) 2.3.S.5 Reference standards or materials (name, manufacturer) 2.3.S.6 Container closure system (name, manufacturer) 2.3.S.7 Stability (name, manufacturer) 3.2.S Drug Substance (name, manufacturer) 3.2.S.1 General information (name, manufacturer) 3.2.S.1.1 Nomenclature (name, manufacturer) 3.2.S.1.2 Structure (name, manufacturer) 3.2.S.1.3 General properties (name, manufacturer) 3.2.S.2 Manufacture (name, manufacturer) 3.2.S.2.1 Manufacturer(s) (name, manufacturer) 3.2.S.2.2 Description of manufacturing process and process controls (name, manufacturer) 3.2.S.2.3 Control of materials (name, manufacturer) 3.2.S.2.4 Control of critical steps and intermediates (name, manufacturer) 3.2.S.2.5 Process validation and/or evaluation (name, manufacturer) 3.2.S.2.6 Manufacturing process development (name, manufacturer) 3.2.S.3 Characterization (name, manufacturer) 3.2.S.3.1 Elucidation of structure and other characteristics (name, manufacturer) 3.2.S.3.2 Impurities (name, manufacturer) 3.2.S.4 Control of drug substance (name, manufacturer) 3.2.S.4.1 Specification (name, manufacturer) 3.2.S.4.2 Analytical procedures (name, manufacturer) 3.2.S.4.3 Validation of analytical procedures (name, manufacturer) 3.2.S.4.4 Batch analyses (name, manufacturer) 3.2.S.4.5 Justification of specification (name, manufacturer) 3.2.S.5 Reference standards or materials (name, manufacturer) 3.2.S.6 Container closure system (name, manufacturer) 3.2.S.7 Stability (name, manufacturer) 3.2.S.7.1 Stability summary and conclusions (name, manufacturer) 3.2.S.7.2 Postapproval stability protocol and stability commitment (name, manufacturer) 3.2.S.7.3 Stability data (name, manufacturer)
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product also mandates the site(s) where manufacturing is permitted and the specific types of processing equipment that can be used in the process. One is required to get prior approval from regulatory bodies to change both the site of manufacture and the type of equipment used to manufacture a drug. For example, if one wants to make a change from using a centrifuge to isolate a solid material during a processing step to using a Nutsche-type of filtration system for that step, the process must be revalidated and prior approval from the various regulatory agencies must be obtained. The basis of these requirements is that such a change could influence the impurity profile if the washing process is more or less efficient, for example, or particle morphology could be affected by solvent residence time or flow. Such seemingly simple changes could, in reality, change the safety of the drug or the rate of delivery of the drug to a patient. The complete set of requirements can be found in the Food and Drug Administration’s (FDA’s) guidance for industry “Changes to an Approved NDA or ANDA” (abbreviated NDA). While initial and subsequent selection of the sites and equipment for manufacture of a drug are at the discretion of the applicant, any significant changes made post-approval come at a tremendous cost to the holder of the NDA. Key point While initial and subsequent selection of the sites and equipment for manufacture of a drug are at the discretion of the applicant, any significant changes made post-approval come at a tremendous cost to the holder of the NDA.
These modules of the application documentation detail the manufacturing steps for the drug substance. A flow diagram for the process should be provided along with a written description of the synthetic route. The specific type of equipment used should also be presented in this part of the application. Examples might include a description of the type of reaction vessels, for example, a glass lined vessel or a steel vessel; also isolation equipment utilized, for example, isolation via centrifugation or through the use of a Nutsche filter-dryer. A critical component of this part is the description of the in-process controls (IPCs) used in the process. Typically, each step of the process is monitored to assure completion of the step without buildup of untoward impurities or degraded material. Ideal IPCs are information rich, reproducible, accurate, and can be easily executed by a chemical operator in a plant setting. A typical IPC might include the conduct of a chromatographic test to assess progress of the reaction. This might be a high performance liquid chromatography (HPLC) method, or a gas chromatographic (GC) analysis. Visual tests can often be effective tools. For example, a color change might be an indication of reaction completeness (presence of the blue color of Na0 in liquid ammonia to signify excess sodium in ammonia in a sodium-ammonia reduction). Often spectroscopic methods such as UV or infrared (IR) are employed. Occasionally pH can be used as an indication of reaction progress. The specifications for the quality attributes required from manufacturers of the key starting materials should be included in this discussion. The analytical methods used to evaluate those materials should also be presented. In addition to key staring materials, the manufacturing description should provide a discussion of the specifications for reagents, solvents, and ancillary materials. Qualification of the sources of the key
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starting materials used for manufacturing of the compound introduced into the process including analytical verification of three representative batches of material from each source should be included in this part of the application. This module of the CTD also presents the rationale for the definition of the starting materials for the process. The team preparing the filing would generally like to define the formal, regulatory starting materials (RSMs) as late in the synthetic sequence as possible as that is the point at which good manufacturing practice (GMP) control is required and changes become time consuming. Materials used in the production of an active pharmaceutical ingredient (API) and which are incorporated as “a significant structural fragment into the structure of the API” are commonly defined as the RSM. It is preferably separated from the API by several synthetic steps. An API starting material should be an article of commerce or it should be well characterized in the chemical literature. It can be a material purchased from one or more suppliers under contract or commercial agreement, or alternatively, an API starting material might be produced in-house. As the sponsor and the FDA often do not agree as to what constitutes an API Starting Material until the end of Phase 2 or even closer to filling of an NDA, a conservative approach would be being aggressive in the initial definition of the starting material to a later stage compound but to conduct some steps prior to the proposed RSM using GMP control. By doing this work, data will be available should the regulatory agency require that the GMP portion of the process begin earlier than what the sponsor had originally proposed. This will save substantial time as regulatory questions can be quickly addressed and for a patented compound, this can be a tremendous financial advantage to a business as the life of patents is finite. In general, it is advisable to define an API starting material and ensure that the position that has been taken is agreeable to the FDA and other regulatory bodies through an early discussion the sponsor can have with the Agency, on that definition. This approach avoids costly surprises late in the registration process. GMP requirements do not apply to steps prior to the defined API starting material. Key point In general, it is advisable to define an API starting material and ensure that the position that has been taken is agreeable to the FDA and other regulatory bodies through an early discussion the sponsor can have with the Agency, on that definition.
The approach of defining “starting material” as a compound found as late in the chemical process scheme as possible affords maximum flexibility in sourcing or manufacturing those materials. It further allows changes to be incorporated in the manufacture of that compound without regulatory impact. GMP requirements do not apply to steps prior to the defined API starting material. Starting materials, reagents, and intermediates (as well as final APIs) need well- defined specifications and appropriate analytical evaluation to control the attributes of the materials used to produce drug substances whether under GMP control or not. These specifications and analytical tests should be information rich and should provide data that assures that the materials introduced into the process are of suitable quality to afford API that meets the clinical requirements. In general, specifications
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for late stage intermediates are more critical and detailed than those for early stage materials or common reagents. Many common materials including solvents have specifications available through various compendial monographs such as the US Pharmacopeia-National Formulary (USP/NF) and the American Chemical Society’s (ACS) Committee on Analytical Reagents through its “Reagent Chemicals” monograph (“ACS Reagent Grade”). These publications also provide standardized methods for the analyses. Key point These specifications and analytical tests should be information rich and should provide data that assures that the materials introduced into the process are of suitable quality to afford API that meets the clinical requirements.
Setting specifications for the final API requires careful thought. At the stage of toxicology studies, material should be of the minimum level of purity acceptable for evaluation and should contain all likely impurities that might be encountered as the process is scaled. The reason for this is that as a process is scaled, equipment is changed from laboratory glassware to fixed equipment in a plant, and impurity profiles can change. With unit operations in a plant often requiring longer times than typically found in the laboratory, impurities can build up and purification can become an issue. For example, heating and cooling processes in a plant reaction vessel are much slower than in a laboratory setting. In a medicinal chemistry laboratory, one has many easy ways and available techniques to use when purifying an agent. Laboratory-scale preparative chromatography is a very common purification technique in medicinal chemistry, as an example. As noted, chromatographic purifications become more challenging in the plant setting as it can be a time consuming process requiring very large volumes and subsequent waste management issues. Additionally, many plant settings operate with Technical Grade solvents rather than ACS grade materials for economic reasons. Decisions about solvent and reagent requirements should be considered at an early stage of the program. Typically for toxicology studies, the API should be in the range of 96–98% purity. As the process is refined and more is learned about the material, the purity should be increased to a level generally above 98% purity. While it might be straightforward to prepare the first few hundred grams at a level of purity of greater than 99%, this can prove very limiting as larger amounts are required and thus produced in plant equipment. Bridging toxicology studies to prove that new impurities are safe from a toxicology perspective are required if new impurities are introduced into the API and cannot be removed. Such studies are quite costly, both in terms of time and money.
Key point Bridging toxicology studies to prove that new impurities are safe from a toxicology perspective are required if new impurities are introduced into the API and cannot be removed. Such studies are quite costly, both in terms of time and money.
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Critical parameters (“critical quality attributes” or CQAs and “critical process parameters” or CPPs) should be determined by experiment and scientific judgment and typically should be based on knowledge derived from research, scale-up batches, or manufacturing experiences. As the drug is approaching regulatory approval (late Phase 2 or early Phase 3), the Chemical Development team meets to conduct a “process risk assessment” or PRA prior to validation. Each process parameter and specification is evaluated and ranked as to its criticality to the product’s quality: a major impact on product quality; some impact on product quality; and no impact on product quality. The other consideration is the probability of the “event” occurring in the manufacturing environment. Does the impacting event happen on every batch of material, happen often, happen rarely, or does the event actually never occur? As the team defines deficiencies in the dataset, further experiments must be conducted to provide a complete understanding of the process. These are either a small set of experiments to define a specific process parameter or a more detailed set of experiments to probe the relationship of a given reaction parameter(s) to several other process parameters. This work is conducted using statistical design of experiments (SDE).
16.2 Statistical evaluation of process variables In the 1920s the British geneticist and statistician, Sir Ronald Fisher, developed the initial concepts of SDE, also referred to as design of experiments or DoE in a more recent update of his work (Fisher, 1971). These concepts provide a formal, rigorous framework to rationally design a set of experiments to relate the quantitative effect of variation of specific parameters with the resulting measured response(s) analyzed using statistical methods. The original concepts were put forth to meet the needs of experimentation in the agricultural field in which he and his colleagues were involved. The basic idea was that there is a simple, underlying geometric structure to such experimentation. Fisher and his colleagues further developed the statistical methods and analyses that became the standard protocol of the discipline. Many chemists are unfamiliar with these techniques. Workers at DuPont were instrumental in moving these concepts into the chemical industry and taught these techniques to many outside organizations beginning in the 1970s (Harris & Lautenberger, 1976). DoE has been shown to be quite useful in the identification of appropriate ranges for critical parameters in a chemical process. The methodology allows multidimensional space to be probed and considers the effect of variation of one parameter on other parameters in the process. It is also very efficient, using a statistically based, mathematical model to generate the interaction of a very large number of parameters through simultaneous variation of multiple parameters within each single experiment rather than changing a single reaction parameter at a time. This allows the conduct of a smaller set of experiments than might otherwise have been contemplated using the single-variable approach. Fortunately, there are a number of commercial, off-the-shelf software products available so that the process chemist does not need to become an expert statistician
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to use these effective techniques. Many in the pharmaceutical industry have used Fusion Pro developed by S-Matrix (https://www.smatrix.com/fusion_pro.html) or JMP Statistical Discovery from SAS (http://www.jmp.com/en_us/home.html) with success. This software is commercially available and parameters such as temperature or stirring rate can be monitored directly through computer based systems. Parameters that might be considered include reaction temperature, mixing rate, cooling rate, and ratio/rate of addition of reagents utilized in the process. While the DoE approach appears complicated at first, this approach proves to afford much more information with fewer experiments than a traditional linear approach where a single variable is explored in a single experiment. When unexpected results are obtained, it is quite probable that some parameters that were not considered critical to the manufacturing process in the initial experimental design are indeed critical. Key point While the DoE approach appears complicated at first, that approach proves to afford much more information with fewer experiments than a traditional linear approach where a single variable is explored in a single experiment.
Parameters that have been determined to be CPPs should be controlled and monitored during process validation studies. The compound produced during process validation should be used to confirm that the impurity profile for each individual lot of API is within the limits set in the specifications and is comparable to, or better than (i.e., lower amounts and/or a smaller number of impurities), the profile of material used for toxicological and early, pivotal clinical studies. A written set of documents or a protocol detailing the strategy planned for process validation should be in place and followed for validating the manufacturing processes for the API. The purpose of the validation work is to ensure that the manufacturing process that has been developed is reliable and provides a product that is homogeneous and consistently meets the predetermined set of specifications each time the process is executed. Among the attributes of the API that should be considered are purity; qualitative and quantitative impurity profiles; physical characteristics including particle size, density, and polymorphic form; moisture and solvent content; homogeneity; and microbial load. Key point Among the attributes of the API that should be considered are purity; qualitative and quantitative impurity profiles; physical characteristics including particle size, density, and polymorphic form; moisture and solvent content; homogeneity; and microbial load.
The protocol should define the scope and purpose of process validation. The number of process validation batches to be prepared should also be addressed. The number of complete batches to be prepared under the protocol has historically been three
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successful, complete batches of the final product; however, regulatory approaches are changing. Today, with a quality by design (QbD) approach becoming the norm, a small number (e.g., 5 or 10) of conformance batches are prepared under protocol with more detailed analytical work being conducted during this “conformance phase” of manufacturing. The development team determines the number of conformance batches needed to assure that the process used is a good representation of the anticipated fullscale, long term manufacturing process. Often, a number of additional analytical tests are performed during validation or process conformance work that might be subsequently eliminated once the process has been shown to be truly consistent. Given the high costs of many APIs, it is acceptable to have executed only one complete batch of final API at the time of the FDA preapproval inspection (PAI) with a commitment to complete the subsequent batches successfully prior to launch of the drug for sale to patients. Analytical test methods that will be used are detailed in the protocol. An example of an analytical test method that might be used during validation but not during routine product release could be multiple IPCs to follow a reaction to completion. These data are collected according to the written description provided in the validation protocol, and if the results obtained during validation are consistent, a number of the IPCs could be eliminated. A detailed discussion of the chemical transformations, unit operations, and a process flow diagram should be included in the validation protocol. The description of the unit operations should include all major processing equipment to be used and reference the appropriate qualification of the equipment (ISPE, 2001). Equipment qualification can be incorporated directly into the validation protocol or by reference to prior reports. Based on the parametric studies that were executed, the CPPs and operating ranges must be described. The protocol should include plans for product sampling. This includes a description of sampling points of the solid material, frequency of removing samples, quantities of each sample required, and procedures for collecting samples. The protocol needs to define criteria by which the executed validation will be deemed acceptable. Deviations from the written plan must also be documented as they occur. The plan should also describe what measures will be taken in the event of a failure. It is wise to execute at least one full-scale batch using the proposed batch production records prior to initiating validation. This is often referred to as a demonstration batch or an engineering batch. This demonstration batch affords confidence that the production procedures, test methods, and specifications have been appropriately written and are easy to execute by the Operations and Analytical Chemistry teams at scale in a plant. Validation must be conducted prior to the commercial distribution of an API and again when there have been significant changes to the manufacturing procedure. Key point It is wise to execute at least one full-scale batch using the proposed batch production records prior to initiating validation. This is often referred to as a demonstration batch or an engineering batch.
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16.3 Current pathways to a process approval— Parametric studies using a QbD approach The FDA and other drug regulatory bodies are encouraging process development activities to be conducted using a QbD process. QbD is referred to as an “enhanced approach” used to collect and evaluate scientific data and to “qualify” a process as opposed to a traditional validation approach where three batches are conducted in an identical manner following a rigid protocol that was approved prior to the start of validation. This approach is summarized in a number of guidance documents issued by the FDA and the ICH as well as in an excellent review article (Yu et al., 2014). The QbD approach is systematic and based on true, high level multivariate “DoEs” as used in a traditional path but recognizes that “process validation” is not a one-time event (i.e., the successful replication of three manufacturing batches of a product—the traditional approach to process validation). It is, instead, an ongoing evolution that begins with initial process development activities and proceeds through scale-up and commercialization until the product is ultimately retired from the market. This approach is focused on developing a more complete understanding of the manufacturing process from a scientific and quality risk-based perspective and ensuring that process knowledge is accumulated, updated, and incorporated into the operation as experience is gained (Gladd, 2014). QbD is most successful when a statistician is part of the Development team. An appropriate design space can be determined and a reliable optimized range for the parameters can be defined with this approach. The design and interpretation of output requires statistical expertise. Fig. 16.1 graphically presents the development of the design space. The orange and yellow areas represent the normal operating range for the process; the blue area represents parameters that, when used,
Develop a “design space” using statistical methods Knowledge space Missing knowledge
Missing knowledge
Design space NOR (normal operating range)
Missing knowledge
Fig. 16.1 QbD approach for process development.
“Multidimensional combination and interaction of inputs (e.g., materials) and process parameters that provide assurance of quality”
“A summary of all process knowledge obtained during product development”
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provide product that meets specifications even if a parameter was out of the “normal operating range”—for example if a reaction was stirred for 4 hours at a given temperature rather than the 3 hours used normally, but the quality is unchanged. As long as one has data to demonstrate that quality is unaffected, one can use the material. The green and gray areas afford product that does not have the required quality attributes. For example, if one determines that stirring for 8 hours at a given temperature affords increased impurity levels, that is shown as the gray area. Often, there are sets of reaction conditions where no data are available. These areas are presented as gaps or “holes” in the knowledge space. The output of such studies is shown in Fig. 16.2. This figure shows the level of impurities as reagent concentration and temperature are varied. Key point The QbD approach is focused on developing a more complete understanding of the manufacturing process from a scientific and quality risk-based perspective and ensuring that process knowledge is accumulated, updated, and incorporated into the operation as experience is gained.
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A robust process accounts for the potential variability in the quality of the starting materials as well as manages the inherent manufacturing constraints of an industrial chemical process. The process is controlled via a “Risk-Based” strategy. The manufacturing process is not locked, allowing for continuous improvements within the design space. This approach provides a high degree of assurance that the API manufacturing process consistently delivers drug substance batches that meet all predetermined CQAs and specifications while offering some flexibility with prescribed operational parameters and scale of manufacturing. There are a number of additional goals for a QbD study. The goal of the study is the systematic collection, assessment, and documentation of operational data so that the knowledge, including the rationale and justification for selected process parameters, is properly documented and is available for use throughout the product life cycle in the marketplace, as market demands increase or decrease and ultimately as the retirement of the product and the end of its life as a useful treatment arrives. These data are summarized in a set of development reports. The steps required for full completion of a QbD development path and subsequent regulatory filing are shown graphically in Fig. 16.3. The QbD knowledge documents are used to establish a validation master plan (VMP) which defines the key activities associated with validation or qualification of the API manufacturing process through each stage of the product life cycle. Specifically, this plan describes the activities, documentation, responsibilities, and general acceptance criteria that will be required at key milestones throughout the development, qualification, and commercialization. In keeping with regulatory guidance, the primary goal of the validation effort is to systematically collect and evaluate scientific data and evidence, from the process design stage through commercial production, which provides a high degree of assurance that the API manufacturing process consistently delivers API batches that meet all predetermined CQAs and specifications. Key point In keeping with regulatory guidance, the primary goal of the validation effort is to systematically collect and evaluate scientific data and evidence, from the process design stage through commercial production, which provides a high degree of assurance that the API manufacturing process consistently delivers API batches that meet all predetermined CQAs and specifications.
In addition to the manufacturing process, this plan is also intended to ensure the appropriate validation or qualification of related supporting systems, equipment, and instruments used for contract manufacturing and laboratory facilities. These include
Determine relationship of parameters
Define the design space with statistical analysis
Define the desired product (API) profile
Define an acceptable range for parameter
Fig. 16.3 Steps along the development path.
Define the range for key parameters
Confirm with high-low experiments
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but are in no sense limited to analytical instrumentation, computer systems used to manage the plant, instruments and inventory of materials, reaction vessels, and filtration and drying equipment as well as the heating, ventilation, and cooling systems of the facility.
16.4 Process performance qualification (validation) activities A product VMP is a written protocol describing the approach and rationale for the validation of the compound manufacturing process that all functional areas have agreed as the appropriate path to prove that the process provides consistent quality material, meeting all specifications. The VMP should cover topics including the facility, utilities, and equipment qualification activities as well as define the people involved in the work. These specific activities are presented in Table 16.2. These tasks are not considered during the academic training of a scientist! Each of these topics has been addressed in this and other chapters in this section. Other topics include, but are not limited to, a reference to approved compound specification(s) and the batch records to be used during production of the material, the specific reaction parameters that will be evaluated, and a plan for how samples will be collected for both in-process tests as well as for isolated intermediates and the final product. This should include a plan to demonstrate that the final batch is homogeneous, describe the analytical methods used for evaluation, and outline the acceptance criteria. If a pause in the execution of the manufacturing process is anticipated, it must be studied during process development. Often, a pause or hold time is a good parameter to consider especially if the manufacturing facility is not a 24/7 setting. The pause can also be used to make certain that the occasional equipment failure can be easily managed. The potential to include reprocessing operations should be considered as part of the process qualification protocol. All qualified sources of starting materials should be included in the discussion of the batches produced.
Activities to be completed as part of validation master plan Table 16.2 Equipment Equipment Equipment Process chemistry Analytical chemistry Cleaning Personnel
The proper qualification of the installation of the equipment (IQ) must be documented The proper qualification of the operation of the equipment (OQ) must be documented; The proper qualification of the performance of the equipment (PQ) must be documented The chemical manufacturing process must be validated The analytical methods must be validated The cleaning procedures must be validated The personnel doing the work must have proper training to actually do the work
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16.5 Accelerated pathways to approval The typical timeframe for what is considered a Standard Review by the FDA, a designation given to drugs that offer slight improvements to currently available therapies, is 10 months. This 10-month goal for a Standard Review was codified in a 2002 amendment to the 1992 Prescription Drug User Fee Act referred to as “PDUFA.” There are, however, various accelerated regulatory pathways that require the same tasks be completed albeit in a very compressed timeframe (Additional information on these pathways can be found in Section D of this book.). Four examples of accelerated pathways to drug regulatory approval include “fast track,” “breakthrough therapy designation,” “priority review,” and “accelerated approval.” A detailed description of these pathways can be found on the FDA’s website as well as in various review articles (Kepplinger, 2015). See: http://www.fda.gov/forpatients/approvals/ fast/ucm20041766.htm. Fast track designation is intended for new drugs to treat a serious condition or infectious disease. Preclinical data for such a potential drug should suggest that the compound has the potential to treat an unmet medical need. Breakthrough therapy designation status is for drug candidates that treat serious conditions. In this case, the potential drug should have some clinical data suggesting that the compound represents a substantial improvement over available drugs. Priority review status is used when a drug candidate has the potential to treat a serious disease with enhanced safety or efficacy versus current treatments. This designation also applies to labeling changes for a pediatric indication or to companies that have a priority review voucher (PRV). These vouchers are obtained if a company develops and receives approval for a neglected or rare pediatric condition. These vouchers can be used by the organization that developed the drug or they can be sold to another organization to be used in conjunction with their application. Accelerated approval status requires that there must be a demonstrated effect on a surrogate—some defined laboratory test or physical observation that correlates as a measure of the positive effect of a drug candidate. Further, for accelerated approval, the compound must, again, treat a serious medical condition. All of these rapid regulatory pathways to drug approval can substantially reduce the time to approval. While all of these programs offer opportunities for rapid approval to market a drug, they do not offer the opportunity to file a chemistry, manufacturing, and controls (CMC) package that is any less complete with respect to the requirements. Thus, the same amount of work must be completed in a greatly reduced period of time.
Key point While all of these programs offer opportunities for rapid approval to market a drug, they do not offer the opportunity to file a CMC package that is any less complete with respect to the requirements. Thus, the same amount of work must be completed in a greatly reduced period of time.
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16.6 Timeline from concept to approval As can be seen from the discussion of the tasks that the Chemical Development team must execute prior to achieving regulatory approval, there is a tremendous of amount of work required. The entire development process, however, can take quite a number of years if a normal approval process is anticipated and the tasks can occur in a programmed fashion, which also affords effective management of cash flow. The various accelerated paths to drug approval still require that the same tasks are completed; the tasks just must be executed in a much shorter timeframe! Fig. 16.4 graphically depicts the pathway from biological concept to regulatory approval of a drug including tasks for the Chemical Development team and the stages of development at which the tasks should be executed. The lower part of the figure shows the actual elapsed time from basic research in biology to demonstration that a novel biological target can actually afford a druggable target and then to subsequent regulatory approval of a drug that can be administered to patients. In the case shown, the druggable target proved to be the proteasome and the first approved drug for that target was bortezomib (Velcade) (Hershko & Ciechanover, 1998; Ward, 2008). The timeline from identification of a novel biological concept or process to approved product is often decades or more—in this specific case approximately 50 years! The Process Development team’s involvement typically begins at the stage when a novel chemical agent is elevated to the status of a drug candidate at the preclinical stage. At that time, larger quantities of materials are required for toxicological evaluation as well as formulation development. The amount of material required at this point is typically in the range of hundreds of grams to many kilograms. The amount of material ultimately required is determined by the potency of the candidate, the formulation of the API into a drug product, bioavailability of the drug, the proposed therapeutic indication, and the dosing schedule of the drug (Fig. 16.5). While the analytical characterization of the material tends to be rudimentary at the stage of preclinical toxicology studies, it is very important to understand enough about the molecule and its properties such that the data generated during toxicology studies are meaningful. As such, analytical methods, in particular, HPLC methods used for an assessment of the purity of the drug substance, should be linear, precise, reproducible, and have an established limit of detection (LOD). The methods will be refined throughout the development cycle. Therefore, while a fully validated analytical method is not needed at the initiation of drug development, the data must be justified from a scientific perspective. It is also necessary to understand the morphology of the product at this point if the product is to be administered in a solid delivery system. When the compound has been shown to have an appropriate safety profile in animal models, human evaluation is set to begin. As one begins evaluation of larger scale preparation of the molecule, a process that is safe and manageable at a multikilogram scale is required. As the scale moves into the range of kilograms, it is time to consider in detail the safety of the chemical operations. From the perspective of GMP compliance requirements, at the stage of Phase 1 clinical trials, cleaning procedures must be considered and protocols should be developed; however, the methods need not be fully validated. As described above, the
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“Manageable” process Process hazard review Cleaning procedures Scientifically sound analytical methods
Parametric studies Stability studies Unit operations Validated analytical methods; Including three lots of API Scale of batch starting material, intermediate, and product specifications; packaging
Fig. 16.4 Timeline: biological concept to marketed drug.
Validatable process One validation batch One batch prior to filing Complete protocol Development report For two additional Impurities identified Batches 12 months stability —3 batches (API shippng and storage only)
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Fig. 16.5 Timeline for bortezomib (Velcade): a real world example.
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analytical methods should be shown to be qualified so that one has confidence that the methods actually provide data as intended. Early stage qualification of analytical methods used to test material for human use per GMP requirements should include a demonstration that the method is linear, precise, accurate, and with defined recovery, specific, LOD/limit of quantification (LOQ), and that the material is stable as an analyte in solution. A small, forced degradation study should be conducted at this stage to ensure that the method is actually “stability-indicating.” A final set of cleaning methods has probably not been defined at this stage of the program. As with analytical methods, they must be shown to be adequate for the intended purpose and properly qualified. As the clinical data for Phase 1 are analyzed and the candidate is elevated into Phase 2 clinical trials, the process must be refined and should substantially resemble the process that is proposed for use in the manufacturing setting. Parametric studies—the study of all parameters of the synthetic or manufacturing process—should be initiated to defend the proposed ranges for the temperature of each reaction, mode and time for reagent additions, and stirring rates for each reaction. In addition, holding times, points where a reaction can be held for further processing at a later time, should be defined. Any other process parameters that the development scientists feel are critical from the studies conducted during process chemistry and engineering design of the industrial route must also be evaluated. As Phase 3 clinical trials are initiated, the process and analytical methods should be locked and fully validated. Preparation for the assembly of the new drug application should be well underway! Analytical methods should be validated and formal stability studies should be undertaken using three separate lots of API. The formal development reports covering all aspects of the chemical process and impurities should be assembled. These reports will be evaluated by regulatory agencies during the review cycle and will be reviewed during onsite inspections. Once the NDA has been filed, the FDA or foreign regulatory agencies, depending on where regulatory filings have occurred, will typically conduct a PAI of the facilities. At the time of the inspection, regulatory agencies expect that the first batch of API at full scale, manufactured according to the validation protocol, would have been completed and the material would have been released. The validation protocol must include plans to complete at least three batches according to the procedure defined in that protocol. Regulatory agencies understand the expense of executing multiple batches. Some firms elect to put off execution of the remaining validation batches until approval appears imminent. More conservative companies will execute all three batches prior to an inspection to assure themselves that no untoward events occur. Failure during validation can delay marketing of the drug to patients. Key point Failure during validation can delay marketing of the drug to patients.
As the NDA review process proceeds and approval of the drug for marketing is anticipated, the execution of the manufacturing process is typically transferred formally from the Process Development team to the Manufacturing department.
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Collectively, those teams, with input from others responsible for evaluating the size of the market and thus demand for the product postapproval, must ensure that batch size has been properly defined and enough material is available to support a successful product launch. While changes to the process, methods, type of processing equipment, and site of manufacture can be initiated at any point, it is important to remember that these changes require a detailed understanding of the regulatory implications so that appropriate responses to the regulatory agency concerned can be made. It is wise not to initiate such changes during the NDA approval process. Depending on the scope of the changes involved, new validation studies will be required, as will completion of additional stability testing with the API that resulted from incorporation of those changes. The material incorporating any changes will need to demonstrate equivalence to the original API. Agencies understand product lifecycle management and permit such changes to processes; however, adequate time must be allowed to obtain proper regulatory approval. Key point While changes to the process, methods, type of processing equipment, and site of manufacture can be initiated at any point, it is important to remember that these changes require a detailed understanding of the regulatory implications so that appropriate responses to the regulatory agency concerned can be made. It is wise not to initiate such changes during the NDA approval process.
16.7 Afterword In summary, there are many tasks that must be executed for a successful approval of an NDA. The tasks are logical and follow a well-defined scientific progression. Attention to the details and well-executed science will ensure success in the approval process. The process does require a tremendous amount of effort and a team with diverse skills. That team includes people with backgrounds in chemistry, engineering, and statistics. The team needs expertise in FDA and other Ministry of Health regulations too. A well-developed system of quality management is mandatory for chemical development and manufacturing in the pharmaceutical industry. Communication skills are not often emphasized during technical educational programs; however, outstanding communication skills are critical to successful drug development and to a successful career! Few early stage people in technical professions appreciate how much writing is involved or how many oral presentations will be made. Clear, concise communication skills are important and paramount to letting others know about the diligent conduct of the studies being described. Assuming that the proposed drug is safe and effective in people, attention to the details and well-executed science will ensure success in the approval process. This guarantees that patients seeking relief from various medical conditions get the help that they need as soon as possible. Helping patients improve the quality of their lives is what this business is ultimately about!
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Key point In summary, there are many tasks that must be executed for a successful approval of an NDA. The tasks are logical and importantly must follow a solid scientific progression. Attention to the details and well-executed science will ensure success in the approval process.
References Fisher, R. (1971). The design of experiments (8th ed.). New York: Hafner Publishing Company. Gladd, T. (2014). QbD: Lessons learned from an FDA filing. Pharmaceutical Online, http:// www.pharmaceuticalonline.com/doc/qbd-lessons-learned-from-an-fda-filing-0001 (February 24, 2014). Harris, H., & Lautenberger, W. (1976). Strategy of experimentation. Wilmington, DE: E.I. Dupont de Nemours & Co. Inc. Short Course Notes. Hershko, A., & Ciechanover, A. (1998). The ubiquitin system. Annual Review of Biochemistry, 67, 425–479. ISPE. (2001). Baseline guide volume 5: Commissioning and qualification. Bethesda, MD: ISPE. Kepplinger, E. E. (2015). FDA’s expedited approval mechanisms for new drug products. Biotechnology Law Report, 34(1), 15–37. Ward, M. (2008). Velcade’s true believers. BioCentury. Cover Story, February 4, 2008, http://www.biocentury.com/biotech-pharma-news/coverstory/2008-02-04/cover-storyproduct-development-velcades-true-believers-a1. Yu, L., Amidon, G., Kahn, M., Hoag, S., Polli, J., Raju, G., et al. (2014). Understanding pharmaceutical quality by design. The AAPS Journal, 16(4), 771–783. http://dx.doi.org/10.1208/ s12248-014-9598-3.
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16.1 Drug substance physical and chemical properties The major “modules” or parts of the New Drug Application (NDA) that concern the Chemical Development team are those covering the “drug substance.” These modules are part of a larger collection of information referred to as the Common Technical Document (CTD) and are generally organized using the International Council on Harmonisation (ICH) prescribed format. Within the “drug substance” module of the CTD, there are a number of major parts and subparts that describe all elements of the chemical process, analytical methods, characterization of all relevant materials including impurities, and requirements of the cleaning processes. The complete list of required sections is presented in Table 16.1. Key point Within the “drug substance” module of the CTD, there are a number of major parts and subparts that describe all elements of the chemical process, analytical methods, characterization of all relevant materials including impurities, and requirements of the cleaning processes.
The tasks that the Chemical Development team must execute are described in this section of the book and are roughly organized following the list of current requirements suggested by the ICH guidelines for a CTD as summarized in their guidance document “M4Q.” Guidance M4Q provides the framework for assembly of regulatory documents in a format that permits effective review by both US and international agencies of the application for approval to market the drug. These modules of a CTD cover nomenclature, chemical structure, and physicochemical properties of the drug substance as well as synthetic and analytical methodology. One is required to provide the International Union of Pure and Applied Chemistry (IUPAC) chemical name of the drug substance and the US Adopted Name (USAN) as well as any common names for the material. A standard graphical representation of the structure is presented along with general physicochemical information about the material. The properties described should include spectroscopic properties, for example the ultraviolet-visible (UV-Vis) spectrum, melting or degradation range, and solubility properties. The rotation for optically active substances should be provided as well as acid–base properties, as pKas, if appropriate. The names and addresses of the manufacturer(s) of the drug substance and all subcontractors involved in the work should be provided. Approval to manufacture a given Managing the Drug Discovery Process. http://dx.doi.org/10.1016/B978-0-08-100625-2.00016-7 © 2017 Elsevier Ltd. All rights reserved.
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Table of contents for sections of a CTD relevant to chemical development Table 16.1
The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality—M4Q(R1) Quality Overall Summary of Module 2, Module 3: Quality 2.3 Quality Overall Summary (QOS) 2.3.S Drug Substance (name, manufacturer) 2.3.S.1 General information (name, manufacturer) 2.3.S.2 Manufacture (name, manufacturer) 2.3.S.3 Characterization (name, manufacturer) 2.3.S.4 Control of drug substance (name, manufacturer) 2.3.S.5 Reference standards or materials (name, manufacturer) 2.3.S.6 Container closure system (name, manufacturer) 2.3.S.7 Stability (name, manufacturer) 3.2.S Drug Substance (name, manufacturer) 3.2.S.1 General information (name, manufacturer) 3.2.S.1.1 Nomenclature (name, manufacturer) 3.2.S.1.2 Structure (name, manufacturer) 3.2.S.1.3 General properties (name, manufacturer) 3.2.S.2 Manufacture (name, manufacturer) 3.2.S.2.1 Manufacturer(s) (name, manufacturer) 3.2.S.2.2 Description of manufacturing process and process controls (name, manufacturer) 3.2.S.2.3 Control of materials (name, manufacturer) 3.2.S.2.4 Control of critical steps and intermediates (name, manufacturer) 3.2.S.2.5 Process validation and/or evaluation (name, manufacturer) 3.2.S.2.6 Manufacturing process development (name, manufacturer) 3.2.S.3 Characterization (name, manufacturer) 3.2.S.3.1 Elucidation of structure and other characteristics (name, manufacturer) 3.2.S.3.2 Impurities (name, manufacturer) 3.2.S.4 Control of drug substance (name, manufacturer) 3.2.S.4.1 Specification (name, manufacturer) 3.2.S.4.2 Analytical procedures (name, manufacturer) 3.2.S.4.3 Validation of analytical procedures (name, manufacturer) 3.2.S.4.4 Batch analyses (name, manufacturer) 3.2.S.4.5 Justification of specification (name, manufacturer) 3.2.S.5 Reference standards or materials (name, manufacturer) 3.2.S.6 Container closure system (name, manufacturer) 3.2.S.7 Stability (name, manufacturer) 3.2.S.7.1 Stability summary and conclusions (name, manufacturer) 3.2.S.7.2 Postapproval stability protocol and stability commitment (name, manufacturer) 3.2.S.7.3 Stability data (name, manufacturer)
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product also mandates the site(s) where manufacturing is permitted and the specific types of processing equipment that can be used in the process. One is required to get prior approval from regulatory bodies to change both the site of manufacture and the type of equipment used to manufacture a drug. For example, if one wants to make a change from using a centrifuge to isolate a solid material during a processing step to using a Nutsche-type of filtration system for that step, the process must be revalidated and prior approval from the various regulatory agencies must be obtained. The basis of these requirements is that such a change could influence the impurity profile if the washing process is more or less efficient, for example, or particle morphology could be affected by solvent residence time or flow. Such seemingly simple changes could, in reality, change the safety of the drug or the rate of delivery of the drug to a patient. The complete set of requirements can be found in the Food and Drug Administration’s (FDA’s) guidance for industry “Changes to an Approved NDA or ANDA” (abbreviated NDA). While initial and subsequent selection of the sites and equipment for manufacture of a drug are at the discretion of the applicant, any significant changes made post-approval come at a tremendous cost to the holder of the NDA. Key point While initial and subsequent selection of the sites and equipment for manufacture of a drug are at the discretion of the applicant, any significant changes made post-approval come at a tremendous cost to the holder of the NDA.
These modules of the application documentation detail the manufacturing steps for the drug substance. A flow diagram for the process should be provided along with a written description of the synthetic route. The specific type of equipment used should also be presented in this part of the application. Examples might include a description of the type of reaction vessels, for example, a glass lined vessel or a steel vessel; also isolation equipment utilized, for example, isolation via centrifugation or through the use of a Nutsche filter-dryer. A critical component of this part is the description of the in-process controls (IPCs) used in the process. Typically, each step of the process is monitored to assure completion of the step without buildup of untoward impurities or degraded material. Ideal IPCs are information rich, reproducible, accurate, and can be easily executed by a chemical operator in a plant setting. A typical IPC might include the conduct of a chromatographic test to assess progress of the reaction. This might be a high performance liquid chromatography (HPLC) method, or a gas chromatographic (GC) analysis. Visual tests can often be effective tools. For example, a color change might be an indication of reaction completeness (presence of the blue color of Na0 in liquid ammonia to signify excess sodium in ammonia in a sodium-ammonia reduction). Often spectroscopic methods such as UV or infrared (IR) are employed. Occasionally pH can be used as an indication of reaction progress. The specifications for the quality attributes required from manufacturers of the key starting materials should be included in this discussion. The analytical methods used to evaluate those materials should also be presented. In addition to key staring materials, the manufacturing description should provide a discussion of the specifications for reagents, solvents, and ancillary materials. Qualification of the sources of the key
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starting materials used for manufacturing of the compound introduced into the process including analytical verification of three representative batches of material from each source should be included in this part of the application. This module of the CTD also presents the rationale for the definition of the starting materials for the process. The team preparing the filing would generally like to define the formal, regulatory starting materials (RSMs) as late in the synthetic sequence as possible as that is the point at which good manufacturing practice (GMP) control is required and changes become time consuming. Materials used in the production of an active pharmaceutical ingredient (API) and which are incorporated as “a significant structural fragment into the structure of the API” are commonly defined as the RSM. It is preferably separated from the API by several synthetic steps. An API starting material should be an article of commerce or it should be well characterized in the chemical literature. It can be a material purchased from one or more suppliers under contract or commercial agreement, or alternatively, an API starting material might be produced in-house. As the sponsor and the FDA often do not agree as to what constitutes an API Starting Material until the end of Phase 2 or even closer to filling of an NDA, a conservative approach would be being aggressive in the initial definition of the starting material to a later stage compound but to conduct some steps prior to the proposed RSM using GMP control. By doing this work, data will be available should the regulatory agency require that the GMP portion of the process begin earlier than what the sponsor had originally proposed. This will save substantial time as regulatory questions can be quickly addressed and for a patented compound, this can be a tremendous financial advantage to a business as the life of patents is finite. In general, it is advisable to define an API starting material and ensure that the position that has been taken is agreeable to the FDA and other regulatory bodies through an early discussion the sponsor can have with the Agency, on that definition. This approach avoids costly surprises late in the registration process. GMP requirements do not apply to steps prior to the defined API starting material. Key point In general, it is advisable to define an API starting material and ensure that the position that has been taken is agreeable to the FDA and other regulatory bodies through an early discussion the sponsor can have with the Agency, on that definition.
The approach of defining “starting material” as a compound found as late in the chemical process scheme as possible affords maximum flexibility in sourcing or manufacturing those materials. It further allows changes to be incorporated in the manufacture of that compound without regulatory impact. GMP requirements do not apply to steps prior to the defined API starting material. Starting materials, reagents, and intermediates (as well as final APIs) need well- defined specifications and appropriate analytical evaluation to control the attributes of the materials used to produce drug substances whether under GMP control or not. These specifications and analytical tests should be information rich and should provide data that assures that the materials introduced into the process are of suitable quality to afford API that meets the clinical requirements. In general, specifications
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for late stage intermediates are more critical and detailed than those for early stage materials or common reagents. Many common materials including solvents have specifications available through various compendial monographs such as the US Pharmacopeia-National Formulary (USP/NF) and the American Chemical Society’s (ACS) Committee on Analytical Reagents through its “Reagent Chemicals” monograph (“ACS Reagent Grade”). These publications also provide standardized methods for the analyses. Key point These specifications and analytical tests should be information rich and should provide data that assures that the materials introduced into the process are of suitable quality to afford API that meets the clinical requirements.
Setting specifications for the final API requires careful thought. At the stage of toxicology studies, material should be of the minimum level of purity acceptable for evaluation and should contain all likely impurities that might be encountered as the process is scaled. The reason for this is that as a process is scaled, equipment is changed from laboratory glassware to fixed equipment in a plant, and impurity profiles can change. With unit operations in a plant often requiring longer times than typically found in the laboratory, impurities can build up and purification can become an issue. For example, heating and cooling processes in a plant reaction vessel are much slower than in a laboratory setting. In a medicinal chemistry laboratory, one has many easy ways and available techniques to use when purifying an agent. Laboratory-scale preparative chromatography is a very common purification technique in medicinal chemistry, as an example. As noted, chromatographic purifications become more challenging in the plant setting as it can be a time consuming process requiring very large volumes and subsequent waste management issues. Additionally, many plant settings operate with Technical Grade solvents rather than ACS grade materials for economic reasons. Decisions about solvent and reagent requirements should be considered at an early stage of the program. Typically for toxicology studies, the API should be in the range of 96–98% purity. As the process is refined and more is learned about the material, the purity should be increased to a level generally above 98% purity. While it might be straightforward to prepare the first few hundred grams at a level of purity of greater than 99%, this can prove very limiting as larger amounts are required and thus produced in plant equipment. Bridging toxicology studies to prove that new impurities are safe from a toxicology perspective are required if new impurities are introduced into the API and cannot be removed. Such studies are quite costly, both in terms of time and money.
Key point Bridging toxicology studies to prove that new impurities are safe from a toxicology perspective are required if new impurities are introduced into the API and cannot be removed. Such studies are quite costly, both in terms of time and money.
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Critical parameters (“critical quality attributes” or CQAs and “critical process parameters” or CPPs) should be determined by experiment and scientific judgment and typically should be based on knowledge derived from research, scale-up batches, or manufacturing experiences. As the drug is approaching regulatory approval (late Phase 2 or early Phase 3), the Chemical Development team meets to conduct a “process risk assessment” or PRA prior to validation. Each process parameter and specification is evaluated and ranked as to its criticality to the product’s quality: a major impact on product quality; some impact on product quality; and no impact on product quality. The other consideration is the probability of the “event” occurring in the manufacturing environment. Does the impacting event happen on every batch of material, happen often, happen rarely, or does the event actually never occur? As the team defines deficiencies in the dataset, further experiments must be conducted to provide a complete understanding of the process. These are either a small set of experiments to define a specific process parameter or a more detailed set of experiments to probe the relationship of a given reaction parameter(s) to several other process parameters. This work is conducted using statistical design of experiments (SDE).
16.2 Statistical evaluation of process variables In the 1920s the British geneticist and statistician, Sir Ronald Fisher, developed the initial concepts of SDE, also referred to as design of experiments or DoE in a more recent update of his work (Fisher, 1971). These concepts provide a formal, rigorous framework to rationally design a set of experiments to relate the quantitative effect of variation of specific parameters with the resulting measured response(s) analyzed using statistical methods. The original concepts were put forth to meet the needs of experimentation in the agricultural field in which he and his colleagues were involved. The basic idea was that there is a simple, underlying geometric structure to such experimentation. Fisher and his colleagues further developed the statistical methods and analyses that became the standard protocol of the discipline. Many chemists are unfamiliar with these techniques. Workers at DuPont were instrumental in moving these concepts into the chemical industry and taught these techniques to many outside organizations beginning in the 1970s (Harris & Lautenberger, 1976). DoE has been shown to be quite useful in the identification of appropriate ranges for critical parameters in a chemical process. The methodology allows multidimensional space to be probed and considers the effect of variation of one parameter on other parameters in the process. It is also very efficient, using a statistically based, mathematical model to generate the interaction of a very large number of parameters through simultaneous variation of multiple parameters within each single experiment rather than changing a single reaction parameter at a time. This allows the conduct of a smaller set of experiments than might otherwise have been contemplated using the single-variable approach. Fortunately, there are a number of commercial, off-the-shelf software products available so that the process chemist does not need to become an expert statistician
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to use these effective techniques. Many in the pharmaceutical industry have used Fusion Pro developed by S-Matrix (https://www.smatrix.com/fusion_pro.html) or JMP Statistical Discovery from SAS (http://www.jmp.com/en_us/home.html) with success. This software is commercially available and parameters such as temperature or stirring rate can be monitored directly through computer based systems. Parameters that might be considered include reaction temperature, mixing rate, cooling rate, and ratio/rate of addition of reagents utilized in the process. While the DoE approach appears complicated at first, this approach proves to afford much more information with fewer experiments than a traditional linear approach where a single variable is explored in a single experiment. When unexpected results are obtained, it is quite probable that some parameters that were not considered critical to the manufacturing process in the initial experimental design are indeed critical. Key point While the DoE approach appears complicated at first, that approach proves to afford much more information with fewer experiments than a traditional linear approach where a single variable is explored in a single experiment.
Parameters that have been determined to be CPPs should be controlled and monitored during process validation studies. The compound produced during process validation should be used to confirm that the impurity profile for each individual lot of API is within the limits set in the specifications and is comparable to, or better than (i.e., lower amounts and/or a smaller number of impurities), the profile of material used for toxicological and early, pivotal clinical studies. A written set of documents or a protocol detailing the strategy planned for process validation should be in place and followed for validating the manufacturing processes for the API. The purpose of the validation work is to ensure that the manufacturing process that has been developed is reliable and provides a product that is homogeneous and consistently meets the predetermined set of specifications each time the process is executed. Among the attributes of the API that should be considered are purity; qualitative and quantitative impurity profiles; physical characteristics including particle size, density, and polymorphic form; moisture and solvent content; homogeneity; and microbial load. Key point Among the attributes of the API that should be considered are purity; qualitative and quantitative impurity profiles; physical characteristics including particle size, density, and polymorphic form; moisture and solvent content; homogeneity; and microbial load.
The protocol should define the scope and purpose of process validation. The number of process validation batches to be prepared should also be addressed. The number of complete batches to be prepared under the protocol has historically been three
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successful, complete batches of the final product; however, regulatory approaches are changing. Today, with a quality by design (QbD) approach becoming the norm, a small number (e.g., 5 or 10) of conformance batches are prepared under protocol with more detailed analytical work being conducted during this “conformance phase” of manufacturing. The development team determines the number of conformance batches needed to assure that the process used is a good representation of the anticipated fullscale, long term manufacturing process. Often, a number of additional analytical tests are performed during validation or process conformance work that might be subsequently eliminated once the process has been shown to be truly consistent. Given the high costs of many APIs, it is acceptable to have executed only one complete batch of final API at the time of the FDA preapproval inspection (PAI) with a commitment to complete the subsequent batches successfully prior to launch of the drug for sale to patients. Analytical test methods that will be used are detailed in the protocol. An example of an analytical test method that might be used during validation but not during routine product release could be multiple IPCs to follow a reaction to completion. These data are collected according to the written description provided in the validation protocol, and if the results obtained during validation are consistent, a number of the IPCs could be eliminated. A detailed discussion of the chemical transformations, unit operations, and a process flow diagram should be included in the validation protocol. The description of the unit operations should include all major processing equipment to be used and reference the appropriate qualification of the equipment (ISPE, 2001). Equipment qualification can be incorporated directly into the validation protocol or by reference to prior reports. Based on the parametric studies that were executed, the CPPs and operating ranges must be described. The protocol should include plans for product sampling. This includes a description of sampling points of the solid material, frequency of removing samples, quantities of each sample required, and procedures for collecting samples. The protocol needs to define criteria by which the executed validation will be deemed acceptable. Deviations from the written plan must also be documented as they occur. The plan should also describe what measures will be taken in the event of a failure. It is wise to execute at least one full-scale batch using the proposed batch production records prior to initiating validation. This is often referred to as a demonstration batch or an engineering batch. This demonstration batch affords confidence that the production procedures, test methods, and specifications have been appropriately written and are easy to execute by the Operations and Analytical Chemistry teams at scale in a plant. Validation must be conducted prior to the commercial distribution of an API and again when there have been significant changes to the manufacturing procedure. Key point It is wise to execute at least one full-scale batch using the proposed batch production records prior to initiating validation. This is often referred to as a demonstration batch or an engineering batch.
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16.3 Current pathways to a process approval— Parametric studies using a QbD approach The FDA and other drug regulatory bodies are encouraging process development activities to be conducted using a QbD process. QbD is referred to as an “enhanced approach” used to collect and evaluate scientific data and to “qualify” a process as opposed to a traditional validation approach where three batches are conducted in an identical manner following a rigid protocol that was approved prior to the start of validation. This approach is summarized in a number of guidance documents issued by the FDA and the ICH as well as in an excellent review article (Yu et al., 2014). The QbD approach is systematic and based on true, high level multivariate “DoEs” as used in a traditional path but recognizes that “process validation” is not a one-time event (i.e., the successful replication of three manufacturing batches of a product—the traditional approach to process validation). It is, instead, an ongoing evolution that begins with initial process development activities and proceeds through scale-up and commercialization until the product is ultimately retired from the market. This approach is focused on developing a more complete understanding of the manufacturing process from a scientific and quality risk-based perspective and ensuring that process knowledge is accumulated, updated, and incorporated into the operation as experience is gained (Gladd, 2014). QbD is most successful when a statistician is part of the Development team. An appropriate design space can be determined and a reliable optimized range for the parameters can be defined with this approach. The design and interpretation of output requires statistical expertise. Fig. 16.1 graphically presents the development of the design space. The orange and yellow areas represent the normal operating range for the process; the blue area represents parameters that, when used,
Develop a “design space” using statistical methods Knowledge space Missing knowledge
Missing knowledge
Design space NOR (normal operating range)
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Fig. 16.1 QbD approach for process development.
“Multidimensional combination and interaction of inputs (e.g., materials) and process parameters that provide assurance of quality”
“A summary of all process knowledge obtained during product development”
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provide product that meets specifications even if a parameter was out of the “normal operating range”—for example if a reaction was stirred for 4 hours at a given temperature rather than the 3 hours used normally, but the quality is unchanged. As long as one has data to demonstrate that quality is unaffected, one can use the material. The green and gray areas afford product that does not have the required quality attributes. For example, if one determines that stirring for 8 hours at a given temperature affords increased impurity levels, that is shown as the gray area. Often, there are sets of reaction conditions where no data are available. These areas are presented as gaps or “holes” in the knowledge space. The output of such studies is shown in Fig. 16.2. This figure shows the level of impurities as reagent concentration and temperature are varied. Key point The QbD approach is focused on developing a more complete understanding of the manufacturing process from a scientific and quality risk-based perspective and ensuring that process knowledge is accumulated, updated, and incorporated into the operation as experience is gained.
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A robust process accounts for the potential variability in the quality of the starting materials as well as manages the inherent manufacturing constraints of an industrial chemical process. The process is controlled via a “Risk-Based” strategy. The manufacturing process is not locked, allowing for continuous improvements within the design space. This approach provides a high degree of assurance that the API manufacturing process consistently delivers drug substance batches that meet all predetermined CQAs and specifications while offering some flexibility with prescribed operational parameters and scale of manufacturing. There are a number of additional goals for a QbD study. The goal of the study is the systematic collection, assessment, and documentation of operational data so that the knowledge, including the rationale and justification for selected process parameters, is properly documented and is available for use throughout the product life cycle in the marketplace, as market demands increase or decrease and ultimately as the retirement of the product and the end of its life as a useful treatment arrives. These data are summarized in a set of development reports. The steps required for full completion of a QbD development path and subsequent regulatory filing are shown graphically in Fig. 16.3. The QbD knowledge documents are used to establish a validation master plan (VMP) which defines the key activities associated with validation or qualification of the API manufacturing process through each stage of the product life cycle. Specifically, this plan describes the activities, documentation, responsibilities, and general acceptance criteria that will be required at key milestones throughout the development, qualification, and commercialization. In keeping with regulatory guidance, the primary goal of the validation effort is to systematically collect and evaluate scientific data and evidence, from the process design stage through commercial production, which provides a high degree of assurance that the API manufacturing process consistently delivers API batches that meet all predetermined CQAs and specifications. Key point In keeping with regulatory guidance, the primary goal of the validation effort is to systematically collect and evaluate scientific data and evidence, from the process design stage through commercial production, which provides a high degree of assurance that the API manufacturing process consistently delivers API batches that meet all predetermined CQAs and specifications.
In addition to the manufacturing process, this plan is also intended to ensure the appropriate validation or qualification of related supporting systems, equipment, and instruments used for contract manufacturing and laboratory facilities. These include
Determine relationship of parameters
Define the design space with statistical analysis
Define the desired product (API) profile
Define an acceptable range for parameter
Fig. 16.3 Steps along the development path.
Define the range for key parameters
Confirm with high-low experiments
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but are in no sense limited to analytical instrumentation, computer systems used to manage the plant, instruments and inventory of materials, reaction vessels, and filtration and drying equipment as well as the heating, ventilation, and cooling systems of the facility.
16.4 Process performance qualification (validation) activities A product VMP is a written protocol describing the approach and rationale for the validation of the compound manufacturing process that all functional areas have agreed as the appropriate path to prove that the process provides consistent quality material, meeting all specifications. The VMP should cover topics including the facility, utilities, and equipment qualification activities as well as define the people involved in the work. These specific activities are presented in Table 16.2. These tasks are not considered during the academic training of a scientist! Each of these topics has been addressed in this and other chapters in this section. Other topics include, but are not limited to, a reference to approved compound specification(s) and the batch records to be used during production of the material, the specific reaction parameters that will be evaluated, and a plan for how samples will be collected for both in-process tests as well as for isolated intermediates and the final product. This should include a plan to demonstrate that the final batch is homogeneous, describe the analytical methods used for evaluation, and outline the acceptance criteria. If a pause in the execution of the manufacturing process is anticipated, it must be studied during process development. Often, a pause or hold time is a good parameter to consider especially if the manufacturing facility is not a 24/7 setting. The pause can also be used to make certain that the occasional equipment failure can be easily managed. The potential to include reprocessing operations should be considered as part of the process qualification protocol. All qualified sources of starting materials should be included in the discussion of the batches produced.
Activities to be completed as part of validation master plan Table 16.2 Equipment Equipment Equipment Process chemistry Analytical chemistry Cleaning Personnel
The proper qualification of the installation of the equipment (IQ) must be documented The proper qualification of the operation of the equipment (OQ) must be documented; The proper qualification of the performance of the equipment (PQ) must be documented The chemical manufacturing process must be validated The analytical methods must be validated The cleaning procedures must be validated The personnel doing the work must have proper training to actually do the work
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16.5 Accelerated pathways to approval The typical timeframe for what is considered a Standard Review by the FDA, a designation given to drugs that offer slight improvements to currently available therapies, is 10 months. This 10-month goal for a Standard Review was codified in a 2002 amendment to the 1992 Prescription Drug User Fee Act referred to as “PDUFA.” There are, however, various accelerated regulatory pathways that require the same tasks be completed albeit in a very compressed timeframe (Additional information on these pathways can be found in Section D of this book.). Four examples of accelerated pathways to drug regulatory approval include “fast track,” “breakthrough therapy designation,” “priority review,” and “accelerated approval.” A detailed description of these pathways can be found on the FDA’s website as well as in various review articles (Kepplinger, 2015). See: http://www.fda.gov/forpatients/approvals/ fast/ucm20041766.htm. Fast track designation is intended for new drugs to treat a serious condition or infectious disease. Preclinical data for such a potential drug should suggest that the compound has the potential to treat an unmet medical need. Breakthrough therapy designation status is for drug candidates that treat serious conditions. In this case, the potential drug should have some clinical data suggesting that the compound represents a substantial improvement over available drugs. Priority review status is used when a drug candidate has the potential to treat a serious disease with enhanced safety or efficacy versus current treatments. This designation also applies to labeling changes for a pediatric indication or to companies that have a priority review voucher (PRV). These vouchers are obtained if a company develops and receives approval for a neglected or rare pediatric condition. These vouchers can be used by the organization that developed the drug or they can be sold to another organization to be used in conjunction with their application. Accelerated approval status requires that there must be a demonstrated effect on a surrogate—some defined laboratory test or physical observation that correlates as a measure of the positive effect of a drug candidate. Further, for accelerated approval, the compound must, again, treat a serious medical condition. All of these rapid regulatory pathways to drug approval can substantially reduce the time to approval. While all of these programs offer opportunities for rapid approval to market a drug, they do not offer the opportunity to file a chemistry, manufacturing, and controls (CMC) package that is any less complete with respect to the requirements. Thus, the same amount of work must be completed in a greatly reduced period of time.
Key point While all of these programs offer opportunities for rapid approval to market a drug, they do not offer the opportunity to file a CMC package that is any less complete with respect to the requirements. Thus, the same amount of work must be completed in a greatly reduced period of time.
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16.6 Timeline from concept to approval As can be seen from the discussion of the tasks that the Chemical Development team must execute prior to achieving regulatory approval, there is a tremendous of amount of work required. The entire development process, however, can take quite a number of years if a normal approval process is anticipated and the tasks can occur in a programmed fashion, which also affords effective management of cash flow. The various accelerated paths to drug approval still require that the same tasks are completed; the tasks just must be executed in a much shorter timeframe! Fig. 16.4 graphically depicts the pathway from biological concept to regulatory approval of a drug including tasks for the Chemical Development team and the stages of development at which the tasks should be executed. The lower part of the figure shows the actual elapsed time from basic research in biology to demonstration that a novel biological target can actually afford a druggable target and then to subsequent regulatory approval of a drug that can be administered to patients. In the case shown, the druggable target proved to be the proteasome and the first approved drug for that target was bortezomib (Velcade) (Hershko & Ciechanover, 1998; Ward, 2008). The timeline from identification of a novel biological concept or process to approved product is often decades or more—in this specific case approximately 50 years! The Process Development team’s involvement typically begins at the stage when a novel chemical agent is elevated to the status of a drug candidate at the preclinical stage. At that time, larger quantities of materials are required for toxicological evaluation as well as formulation development. The amount of material required at this point is typically in the range of hundreds of grams to many kilograms. The amount of material ultimately required is determined by the potency of the candidate, the formulation of the API into a drug product, bioavailability of the drug, the proposed therapeutic indication, and the dosing schedule of the drug (Fig. 16.5). While the analytical characterization of the material tends to be rudimentary at the stage of preclinical toxicology studies, it is very important to understand enough about the molecule and its properties such that the data generated during toxicology studies are meaningful. As such, analytical methods, in particular, HPLC methods used for an assessment of the purity of the drug substance, should be linear, precise, reproducible, and have an established limit of detection (LOD). The methods will be refined throughout the development cycle. Therefore, while a fully validated analytical method is not needed at the initiation of drug development, the data must be justified from a scientific perspective. It is also necessary to understand the morphology of the product at this point if the product is to be administered in a solid delivery system. When the compound has been shown to have an appropriate safety profile in animal models, human evaluation is set to begin. As one begins evaluation of larger scale preparation of the molecule, a process that is safe and manageable at a multikilogram scale is required. As the scale moves into the range of kilograms, it is time to consider in detail the safety of the chemical operations. From the perspective of GMP compliance requirements, at the stage of Phase 1 clinical trials, cleaning procedures must be considered and protocols should be developed; however, the methods need not be fully validated. As described above, the
Toxicology studies
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Mfg. batch definition
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Drug discovery program: medicinal chemistry, pharmacology, pre-clinical stability
“Manageable” process Process hazard review Cleaning procedures Scientifically sound analytical methods
Parametric studies Stability studies Unit operations Validated analytical methods; Including three lots of API Scale of batch starting material, intermediate, and product specifications; packaging
Fig. 16.4 Timeline: biological concept to marketed drug.
Validatable process One validation batch One batch prior to filing Complete protocol Development report For two additional Impurities identified Batches 12 months stability —3 batches (API shippng and storage only)
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MyoGenics founded to probe proteasome
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Fig. 16.5 Timeline for bortezomib (Velcade): a real world example.
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Nobel Prize >550,000 to Rose, patients Hershko, and treated Chiechanover for proteasome
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analytical methods should be shown to be qualified so that one has confidence that the methods actually provide data as intended. Early stage qualification of analytical methods used to test material for human use per GMP requirements should include a demonstration that the method is linear, precise, accurate, and with defined recovery, specific, LOD/limit of quantification (LOQ), and that the material is stable as an analyte in solution. A small, forced degradation study should be conducted at this stage to ensure that the method is actually “stability-indicating.” A final set of cleaning methods has probably not been defined at this stage of the program. As with analytical methods, they must be shown to be adequate for the intended purpose and properly qualified. As the clinical data for Phase 1 are analyzed and the candidate is elevated into Phase 2 clinical trials, the process must be refined and should substantially resemble the process that is proposed for use in the manufacturing setting. Parametric studies—the study of all parameters of the synthetic or manufacturing process—should be initiated to defend the proposed ranges for the temperature of each reaction, mode and time for reagent additions, and stirring rates for each reaction. In addition, holding times, points where a reaction can be held for further processing at a later time, should be defined. Any other process parameters that the development scientists feel are critical from the studies conducted during process chemistry and engineering design of the industrial route must also be evaluated. As Phase 3 clinical trials are initiated, the process and analytical methods should be locked and fully validated. Preparation for the assembly of the new drug application should be well underway! Analytical methods should be validated and formal stability studies should be undertaken using three separate lots of API. The formal development reports covering all aspects of the chemical process and impurities should be assembled. These reports will be evaluated by regulatory agencies during the review cycle and will be reviewed during onsite inspections. Once the NDA has been filed, the FDA or foreign regulatory agencies, depending on where regulatory filings have occurred, will typically conduct a PAI of the facilities. At the time of the inspection, regulatory agencies expect that the first batch of API at full scale, manufactured according to the validation protocol, would have been completed and the material would have been released. The validation protocol must include plans to complete at least three batches according to the procedure defined in that protocol. Regulatory agencies understand the expense of executing multiple batches. Some firms elect to put off execution of the remaining validation batches until approval appears imminent. More conservative companies will execute all three batches prior to an inspection to assure themselves that no untoward events occur. Failure during validation can delay marketing of the drug to patients. Key point Failure during validation can delay marketing of the drug to patients.
As the NDA review process proceeds and approval of the drug for marketing is anticipated, the execution of the manufacturing process is typically transferred formally from the Process Development team to the Manufacturing department.
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Collectively, those teams, with input from others responsible for evaluating the size of the market and thus demand for the product postapproval, must ensure that batch size has been properly defined and enough material is available to support a successful product launch. While changes to the process, methods, type of processing equipment, and site of manufacture can be initiated at any point, it is important to remember that these changes require a detailed understanding of the regulatory implications so that appropriate responses to the regulatory agency concerned can be made. It is wise not to initiate such changes during the NDA approval process. Depending on the scope of the changes involved, new validation studies will be required, as will completion of additional stability testing with the API that resulted from incorporation of those changes. The material incorporating any changes will need to demonstrate equivalence to the original API. Agencies understand product lifecycle management and permit such changes to processes; however, adequate time must be allowed to obtain proper regulatory approval. Key point While changes to the process, methods, type of processing equipment, and site of manufacture can be initiated at any point, it is important to remember that these changes require a detailed understanding of the regulatory implications so that appropriate responses to the regulatory agency concerned can be made. It is wise not to initiate such changes during the NDA approval process.
16.7 Afterword In summary, there are many tasks that must be executed for a successful approval of an NDA. The tasks are logical and follow a well-defined scientific progression. Attention to the details and well-executed science will ensure success in the approval process. The process does require a tremendous amount of effort and a team with diverse skills. That team includes people with backgrounds in chemistry, engineering, and statistics. The team needs expertise in FDA and other Ministry of Health regulations too. A well-developed system of quality management is mandatory for chemical development and manufacturing in the pharmaceutical industry. Communication skills are not often emphasized during technical educational programs; however, outstanding communication skills are critical to successful drug development and to a successful career! Few early stage people in technical professions appreciate how much writing is involved or how many oral presentations will be made. Clear, concise communication skills are important and paramount to letting others know about the diligent conduct of the studies being described. Assuming that the proposed drug is safe and effective in people, attention to the details and well-executed science will ensure success in the approval process. This guarantees that patients seeking relief from various medical conditions get the help that they need as soon as possible. Helping patients improve the quality of their lives is what this business is ultimately about!
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Key point In summary, there are many tasks that must be executed for a successful approval of an NDA. The tasks are logical and importantly must follow a solid scientific progression. Attention to the details and well-executed science will ensure success in the approval process.
References Fisher, R. (1971). The design of experiments (8th ed.). New York: Hafner Publishing Company. Gladd, T. (2014). QbD: Lessons learned from an FDA filing. Pharmaceutical Online, http:// www.pharmaceuticalonline.com/doc/qbd-lessons-learned-from-an-fda-filing-0001 (February 24, 2014). Harris, H., & Lautenberger, W. (1976). Strategy of experimentation. Wilmington, DE: E.I. Dupont de Nemours & Co. Inc. Short Course Notes. Hershko, A., & Ciechanover, A. (1998). The ubiquitin system. Annual Review of Biochemistry, 67, 425–479. ISPE. (2001). Baseline guide volume 5: Commissioning and qualification. Bethesda, MD: ISPE. Kepplinger, E. E. (2015). FDA’s expedited approval mechanisms for new drug products. Biotechnology Law Report, 34(1), 15–37. Ward, M. (2008). Velcade’s true believers. BioCentury. Cover Story, February 4, 2008, http://www.biocentury.com/biotech-pharma-news/coverstory/2008-02-04/cover-storyproduct-development-velcades-true-believers-a1. Yu, L., Amidon, G., Kahn, M., Hoag, S., Polli, J., Raju, G., et al. (2014). Understanding pharmaceutical quality by design. The AAPS Journal, 16(4), 771–783. http://dx.doi.org/10.1208/ s12248-014-9598-3.