The Odd Couple – Part 7: Authoring the Composition and Pharmaceutical Development Modules

The Odd Couple – Part 6: Authoring the Stability of Drug Substance and Product Modules
August 4, 2020
How to File an Invincible IND Application
September 1, 2020

The Odd Couple – Part 7: Authoring the Composition and Pharmaceutical Development Modules

This full Series follows our initial Primer blogs: Constructing the CTD Quality Module 3, and Quality Overall Summary: Reviewers Guide. For the purposes of this blog series, it will be necessary to produce an admittedly unbalanced summary that shortchanges some sections of the Quality Module but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application. I have therefore focused discussion on selected aspects from a remarkably diverse and technical exercise, which is the production of the CTD Quality Module.

The CTD Module 3

Though the content of these modules is generally well defined, according to the various guidance documents previously referred to, considerable latitude for assimilating, discussing, comparing, and contrasting data is allowed and even encouraged. There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.  

CTD Module 3 is well defined containing both drug substance (active ingredient) and drug product sections, with each containing required presentations of drug technical information, processes and key parameters, and various justification supported by qualification and validation studies.

This data and these reports provide the detailed evidence that a drug’s characteristics are well defined and well controlled, such that one can assure that the next lot produced is essentially the same as the last lot. Drug manufacture control and reproducibility is the essential message that Module 3 must convey if Agency reviewers are to conclude that a new drug application merits approval.

Sponsors have latitude in how data are presented, and how important messages are formatted in the compilation of a CTD application.

Preparation of CTD submissions for various regulatory authorities should be geared toward meeting those unique regulatory standards.

Pharmaceuticals (both Synthetically and Biotechnology-derived) are being developed by many sponsors whose management teams have varying degrees of familiarity or experience with the regulatory requirements for these challenging products.

A few sections are of particular interest. Section 3.2.S.2.6 Manufacturing Process Development as discussed in a previous blog and 3.2.P.2 Pharmaceutical Development include the development work that supports the compliance data for the module, and are unique in that they tell a story rather than simply being a collection of data.

For most drugs, the manufacturing development program has truly evolved, often such that substantial differences exist between a drug substance or product early in development versus that which is proposed for marketing.

The challenge inherent in describing development changes is to convince Agency reviewers that it is appropriate to consider and to integrate nonclinical and clinical data obtained at various points during development, having studied drugs that might have been considerably different at these points.

Part of the difficulty in assimilating a cohesive and coherent Module 3 is the common situation that the generation of CMC data comes from various sources, especially in P.2 Pharmaceutical Development. Although sometimes all development is undertaken in-house, it is more common that the module must rely on the contributions of both in-house and outside parties.

As drug development accelerates, the pressure to generate batches of drug substance and drug product for nonclinical and clinical trials increases greatly. GMP standards are high, including documentation requirements for the analytical and stability programs supporting manufacturing.

At the same time, technical experts in manufacturing are investigating more efficient process schemes and, frequently, look to alternate contractors to reduce costs and to prevent being restricted to a single-sourced strategy, if feasible.

All of these changes require documentation and evidence of control, if possible, beginning at the initiation of the project and planned proactively as far out in time as possible. For purposes of putting together Module 3, it is particularly important to get it right from the start.

It is extraordinarily difficult to have to go back in time to some primary source and try to reconstruct retrospectively, particularly if the people responsible are no longer available or if other links are missing.

A final aspect of the Development conformance sections that contribute to Module 3 distinctiveness is the necessity for development reports. Pharmaceutical development reports include drug substance (active ingredient), drug product, and analytical reports.

These reports need to tell the historical story of the evolution of these three development aspects during the lifetime of the product’s development.

Agency reviewers need to understand clearly how the drug has evolved and, ultimately, be able to agree that all nonclinical and clinical data derived during development are somehow informative and relevant to the drug product that ultimately would reach the market.

Because it is rarely the case that a drug remains the same during the years of development, it is important that all ongoing chemistry and manufacturing changes are documented, and the ramifications of product differences understood.

When the history of changes has led to improved purity and tightening of release specifications the story is easy to tell; if this is not the case, considerable creativity may be necessary. Development reports may benefit from the input of the English major as much as the chemist.

If development reports are poorly prepared or unconvincing, the result can easily be an almost endless cycle of Agency queries and sponsor responses, prolonging the review cycle and delaying approval times.

In case you’re apprehensive that this sort of “odd couple” has varying degrees of familiarity or experience with developing the CMC Submission for these products, I will take a look at the principles responsible for administration of the standards everyone needs, the “Guidances”, and work to use these and recent practice as the “guidance counselor”. The CTD Module 3

CONTROL OF DRUG PRODUCT

P.1. DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

A description of the drug product qualitative/quantitative composition should provide a list of all ingredients, including solvents used in the manufacture of the drug product. The components of the formulation should be categorized in your submission according to their function. The drug product should be categorized according to its route of administration. 

The functional aspects of each component of the drug product are central to the development rationalization of the formulation and serve as reference points in the examination of supportive development data. An understanding of each component’s function allows for data-driven risk assessment during the marketing application review.

The functional aspects of excipients can be divided into four basic categories that may impact (1) stability of the drug substance, (2) physical characteristics, (3) in vivo absorption, and (4) manufacturability. While these general classifications can be applied, excipients may have multifunctional roles, and, thus, the degree of physical characterization of the excipient is dependent upon complete elucidation of the excipient function.

Excipient Impact on Stability

No formulation is the same. Consider, in the case of excipients used as stabilizing agents, moisture-induced degradation commonly is associated with dosage forms and may entail simple hydrolysis, or, in some cases, water may serve to increase molecular mobility and, hence, reactivity of the drug substance.

It has been hypothesized that excipients with a strong affinity for water may function to keep water away from the active drug substance and prevent moisture-induced degradation. However, excessive moisture uptake by the excipient may, in contrast, facilitate degradation of the active ingredient. Something to think about in the presentation of any data.

Physical Roles of Excipients

Excipients play practical physical roles in dosage forms, serving as diluents to allow formulation of appropriately sized tablets, disintegrants to enhance formulation disintegration, and coatings to protect the tablet or mask undesirable organoleptic qualities of the drug substance.

Excipients and In Vivo Effects

Excipients have the potential to impact the in vivo absorption of drugs. The factors that may influence bioavailability include the in vivo disintegration and dissolution of the dosage form and the excipient influence on physiological processes and factors such as pH of the microenvironment, gastrointestinal tract (GI) transit time, and stability of the drug substance in the GI tract.

The potential impact of excipients is thus related, in part, to the solubility and permeability characteristics of the drug substance. A detailed understanding of the drug substance’s physicochemical characteristics is essential to the elucidation of the functional role of the dosage form excipients and should be discussed.

Excipients in the Manufacturing Process

Preformulation study data allow the reviewer to confirm the assignment of the critical quality attributes of the excipient relative to the excipient’s purported role in dosage form functionality. The data should demonstrate, through controlled experiments, the functional role of the excipient and any physicochemical characteristics of the excipient critical to its function in the formulation.

P.2. PHARMACEUTICAL DEVELOPMENT

Pharmaceutical development information provides the scientific rationale for the formulation development approach through to the final development and justification of a suitable dosage form.This generalized approach provides information pertinent to preformulation applications for most dosage forms. 

The discussion here should be generalized to cover either your solid and liquid (including parenteral) formulations. Formulations can be categorized according to the route of administration and include oral, rectal, vaginal, inhalation, topical, transdermal, intraocular, intranasal, and parenteral drug products. 

Regulatory guidance describes only limited detail of the requirements for the data sets associated with pharmaceutical development. Although more detailed guidance is available for the toxicological assessment of excipients, the detailed scientific approach to formulation development and justification is left to the discretion of the development organization, and the level of detail is dependent upon the complexity of the dosage form.

The reviewer should be able to assess the availability of formulation development study data, with an emphasis on potential interactions between the drug substance and excipients that could impact dosage form behavior.

P.2.1 Components of the Drug Product

Drug Substance

Drug substance characterization is Characterization Blog. The properties of the drug substance can have a significant effect on the physical and chemical behavior of the drug product. A review of the drug substance physical and chemical properties should be performed in relation to the excipient characteristics.

The ultimate influence of the drug substance particle characteristics on drug product performance will depend, in part, on the characteristics of the excipients and should be discussed.

Excipients

Excipients typically are the major fraction of the solid dosage form. As such, the characterization of the individual drug/excipient interaction is an important part of understanding the overall behavior of the dosage form.

It is well known from studies of drug substances that water associated with the drug substance solid can influence chemical degradation rates, dissolution, powder flow, and other physical properties.

Likewise, the physical state of the excipient can impact the performance of the drug product. The regulatory status of the excipient is an additional consideration. In the United States, an excipient that is ‘‘generally recognized as safe,’’ (GRAS) for its intended use can be exempted from premarket approval requirements

If the excipients are not GRAS or do not have food additive status, have the excipients been used in approved products in the United States or Europe?Are the excipients well characterized with regard to safety? 

Is the use of this excipient in pharmaceutical products documented in the literature? In the absence of such information, the safety profile of the excipient must be demonstrated, thereby adding an additional regulatory burden.

The source of excipients used in the drug product should be considered. A general compendial guidance, such as the United States Pharmacopeia (USP), recommends that suppliers of excipients meet current good manufacturing practices (cGMP) requirements. If the supplier has not received a cGMP inspection by a regulatory body, an in-house quality inspection of the facility should be performed in advance of the application review.

Adequate control during the excipient manufacturing process provides increased certainty that the quality attributes of the excipient determined to be critical will continue to be met. While the manufacturer can assure meeting the compendial requirements of the excipient, it is not possible for the monograph to include every possible impurity (considering that monograph substances may be prepared by various methods of manufacture).

It is, therefore, important for the source of the excipient to be controlled and the quality of the material to be characterized beyond basic compendial requirements to include those critical quality attributes (CQA) that impact the drug product performance. This should be documented.

What is the synthetic route of the excipient? What are common impurities of the process? Are the impurities characterized? How does the manufacturer control these impurities? Do these impurities have chemical characteristics that would indicate the potential for interaction with the drug substance? What are the physical characteristics of the excipient (e.g., shape, size)? This should all be discussed in the application, especially when and where required.

Solid Dosage Forms

Some incompatibilities of drug substance functional groups and excipients are documented in the literature and can provide guidance in the design phase of compatibility studies.

This discussion should include a review of the fundamental chemistry of the drug substance and the excipients. Are any potential incompatibilities apparent?

For example, solid-state reactions in the dosage form can occur when the drug substance intrinsically is reactive and may be accelerated by interaction with excipients (chemical/physical interaction) or induced by excipients (where the excipient does not chemically interact but promotes the degradation of the drug substance).

Liquid Dosage Forms

Liquid formulations span a variety of dosage forms, including oral liquids and parenteral formulations. The requirements for oral liquids may be considered a subset of the requirements of liquid parenterals.

A review of commonly used excipients in approved parenteral products should be compiled that classifies any excipients into any of the seven categories based upon their function.

The excipients are categorized as solvents, thickening agents, chelating agents, antioxidants (including reducing agents and antioxidant synergists), preservatives, buffers, and bulking agents. The compiled list represents a starting point for the reviewer to examine potential compatibility of the parenteral drug substance with commonly used excipients and may be applicable to other liquid products such as oral liquid formulations.

For liquid formulations, the compatibility study of the drug/excipient mixture with the packaging system is an essential activity that should be documented due to the intimate contact between the product and the container. For powder-fill systems, an approach similar to that of solid-dosage systems is advised with regard to compatibility testing, albeit in the presence of the proposed packaging system.

In addition, products for reconstitution must demonstrate adequate compatibility with proposed diluents.

For sterile liquid dosage formulations, the stability of the formulation when autoclaved is an important consideration with regulatory implications. Products that are intended to be sterile should be sterilized in their final container.

Well-documented development efforts are essential to defending the need for a formulation that cannot undergo heat sterilization. For nonsterile liquids, assurance of acceptable microbial bioburden during manufacture and throughout shelf life should be demonstrated.

As with other excipients, the physical and chemical compatibility of the preservative or antioxidant should be demonstrated. In addition, the level of antioxidant or preservative should be justified with regard to safety.

Suspension formulations may be developed when the drug substance has inadequate solubility to be formulated as a solution or if the suspension of the drug is more stable than the solution of the drug substance.

Some of the characteristics of acceptable suspensions (beyond requisite stability requirements) include nonrapid settling of particles (sedimentation), re-suspendibility, and homogeneity of resuspended mixtures. Particle size of the drug substance in the suspension is an important aspect of the formulation and should be discussed.

P.2.2. Excipient Characterization and Critical Quality Attributes

The identification of critical physicochemical characteristics via compatibility studies allows for the development of methodologies to control those aspects of the excipient that are critical to product performance.

The reviewer should be able to examine the data generated during preformulation studies to assess the validity of the conclusions regarding the assignment of CQAs to the excipient components.

The view of functionality as a critical aspect in determining excipient quality has been amply argued and demonstrated in the literature. Adequate characterization of the critical quality attributes of selected excipients is crucial to the formulation development process.

The solid-state characteristics of excipients used in solid dosage forms should be well defined. The level of characterization and control of various physicochemical aspects of the excipient is dependent upon the outcome of the preformulation studies.

The chemical characteristics of excipients can influence drug product behavior. Beyond chromatographic analysis of excipients, excipient characterization can be approached by using a variety of spectroscopic techniques, including IR, near-IR, and Raman spectroscopy.

Volatile impurities (e.g., residual solvents) should be identified by using the thermal-spectroscopic technique of TG-IR. Residual solvents may be an important feature regarding the performance of the drug product, especially with regard to dosage forms formulated with copolymers.

Definition of the critical quality attributes of the excipient and the drug substance will enable the implementation of appropriate controls as manufacturing process development proceeds. The reviewer should be assured that the critical quality attributes of each excipient are well defined.

Preformulation data should support the selection of each CQA and its potential impact on drug product performance.

P.2.3. Manufacturing Process Development

A discussion of the manufacturing process development should include an emphasis on the reproducibility of the critical quality attributes of the drug product. Changes to the method of manufacture should be detailed as the process moved from initial phase 1 studies through to the final commercial process.

The discussion should focus on any process changes made subsequent to the first clinical study. A review of all clinical studies and the manufacturing process used to provide the clinical supplies should be provided.

Manufacturing process development begins at the small scale and proceeds to a minimum of 10% full production scale for pivotal clinical studies and registration stability studies. Ultimately full-scale production batches (sometimes referred to as demonstration or engineering batches) are made prior to validation of the process.

The development studies should clearly detail the effect of process changes on critical quality attributes associated with the intermediates and the finished product. There are a variety of multivariate methods that can be used in process development studies.

The experimental designs rely on a thorough understanding of the process and its critical attributes. One approach is to follow the hazard analysis and critical control points system for identifying and controlling critical process steps.

Reworking of a drug product should include a detailed analysis of the impact on the drug product critical attributes. Reworking of tablets, for example, can have an impact on formulation flowability, tablet crushing strength, and disintegrations times. The rework process should be described in detail with proposed manufacturing batch documents.

For sterile products, a review of the presterilization bioburden data should be performed because this is essential to demonstrate the ruggedness of the process. For nonsterile liquid products, a review of the microbial limits testing data should be performed and can be provided. of the defined cycles for primary and secondary drying.

P.2.5 Container Closure System

For stable products with no sensitivity to environmental conditions (e.g., moisture or oxygen) the justification of the package requires data sufficient to show the acceptability of the drug product’s physicochemical attributes during storage.

Based upon the knowledge of the physical and chemical behavior of the drug product in preformulation and subsequent stability studies of model formulations, an appropriate package should be selected.

For oxygen- or moisture sensitive products, a package that provides an effective barrier must be demonstrated. In addition, it may be necessary to demonstrate via headspace analysis that the packaging conditions provide an acceptable internal atmosphere or that the addition of some appropriate inert gas is necessary.

The selection of a product package for liquids is linked intrinsically to the formulation and should be part of the multivariate analysis in the design of formulation development and optimization studies.

The selection of rubber stoppers for parenteral liquids typically entails the examination of extractables from the stopper in contact with the parenteral base formulation.

P.2.5 Microbiological Attributes

The FDA states in its microbiological inspection guide that each company is expected to develop microbial specifications for nonsterile products.

Microbial attributes are often thought to apply mainly to sterile drug products. However, a major focus of regulatory drug applications is the safety of the product. Associated with the safety of nonsterile products is the potential microbiological burden introduced by the raw materials and/or the processing environment.

The quality expectations for sterile products are clearly delineated in the United States and European Union (EU) In addition, the product must meet compendial requirements (i.e., USP and European Pharmacopoeia). A strategy to control endotoxins in excipients also must be developed, with appropriate limits, dependent upon the route of administration and dosing regimen of the sterile product.

Adequate process design and implementation of cGMPs provide assurance of acceptable bioburden or sterility because testing can identify only catastrophic failures. A review of the process design and the product flow should be performed to assure that appropriate techniques are used to produce drug products of acceptable microbial standards.

P.2.6 Compatibility

The compatibility of the drug product with reconstitution diluents or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labeling.

For the purposes of this blog series, it was necessary to produce an admittedly unbalanced summary that shortchanges some sections of the Quality Module but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application. I have therefore focused discussion on selected aspects from a remarkably diverse and technical exercise, which is the production of the CTD Quality Module.

Though the content of these modules is generally well defined, according to the various guidance documents previously referred to, considerable latitude for assimilating, discussing, comparing, and contrasting data is allowed and even encouraged. There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.

Ultimately, the timeliness of an Agency’s review and approval status of a drug’s Quality section is best served by preparation of a well-designed Quality Module. Insights and recommendations from the past fifteen years are provided here to help maximize the potential for a successful outcome.

Common Technical Document SectionRecommendations per Guidance(GMP) Source Documents Electronic Y/N
3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product a description of the drug product and its composition should be provided information provided should include, for example: description of the dosage form composition, the function of the components, and a reference to their quality standards (e.g., compendial monographs or manufacturer’s specifications) descriptionof accompanying reconstitution diluents type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable reference ICH guidances Q6A and Q6B.Formula/Ingredients Export CPD Composition sheet
3.2.P.2 Pharmaceutical DevelopmentContain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes, and usage instructions are appropriate for the purpose specified in the application Studies described in this section should be distinguished from routine control tests conducted according to specifications Identify and describe the formulation and process attributes that can influence batch reproducibility, product performance, and drug product quality Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical Development section  Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the application reference ICH guidances Q6A and Q6B.Export CPD CMC (Registration/Filing)  Pharmaceutical Development Reports – (formulation specific) Optimization Reports  Dosage form decisions
3.2.P.2.1 Components of the Drug Product   
3.2.P.2.1.1 Drug Substance compatibility of the drug substance with the excipients listed in 3.2.P.1 should be discussed key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the drug substance that can influence the performance of the drug product should be discussed.Compatibility studues ID of degradation products Water content, solubility, particle size distribution, polymorphic or solid state form Reports
3.2.P.2.1.2 ExcipientsExcipients listed in 3.2.P.1, their concentration, and the characteristics that can influence the drug product performance should be discussed relative to their respective functions.Excipient Specifications Excipient Certificates of Analysis
Qualification reports (GRAS) status compendial
3.2.P.2.2 Drug Product 

3.2.P.2.2.1 Formulation DevelopmentA brief summary describing the development of the drug product should be provided, taking into consideration the proposed route of administration and usage differences between clinical formulations and the formulation (i.e., composition) described in 3.2.P.1 should be discussed Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate.Export CPD Pharmaceutical Development Protocols, Reports
3.2.P.2.2.2 OveragesAny overages in the formulations described in P1 should be justified.Carton and Vial Label Sets
3.2.P.2.2.3 Physicochemical and Biological Properties parameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.DP Formulation, Stability Data Summaries and Stability Study Protocols Bioactivity or Potency Assay Development work
3.2.P.2.3 Manufacturing Process Development  selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained Where relevant, the method of sterilization should be explained and justified. Differences between the manufacturing processes used to produce pivotal clinical batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.Export CPD CMC (Registration/Filing) Manufacturing Technical Reports Pilot Plant Development Report Tech Transfer Protocol, Reports Process validation (CQA’a, CPP’s, sterility assurance)  Batch records (complete with deviations and supporting documents), COA’s, testing and release records

3.2.P.2.4 Container Closure System suitability of the container closure system (described in 3.2.P.7) for the storage, transportation (shipping), and use of the drug product should be discussed discussion should consider, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption tocontainer and leaching), safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).Packaging Components Suitability studies (Extractables/Leachables)
Container Closure Specifications Container Closure Diagrams Container Closure Certificates of Analysis
3.2.P.2.5 Microbiological Attributesmicrobiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for nonsterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives for sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.Compatability Data/ Microbial Stability Reports
3.2.P.2.6 Compatibility compatibility of the drug product with reconstitution diluents or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labeling.Compatability Data 

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