Handbook of pharmaceutical manufacturing formulations, third edition: volume two, uncompressed solid products

Handbook of Pharmaceutical Manufacturing Formulations, Third Edition Volume Two, Uncompressed Solid Products Handbook of Pharmaceutical Manufacturing Formulations Volume Two, Uncompressed Solid Produc.

regulatory and Manufacturing Guidelines

Module 2 should begin with a general introduction to the pharmaceutical, including its pharmacological class, mode of action, and proposed clinical use In general, the Introduction should not exceed one page.

Module 2 should contain seven sections in the following order:

• Nonclinical Written and Tabulated Summaries

The organization of these summaries is described in

Information on Quality should be presented in the structured format described in Guideline M4Q.

The nonclinical study reports should be presented in the order described in Guideline M4S.

The human study reports and related information should be presented in the order described in Guideline M4E.

The overall organization of the CTD is presented on the following pages.

Diagrammatic Representation of the Organization of the ICH CTD

ORGANIZATION OF THE COMMON TECHNICAL

DOCUMENT FOR THE REGISTRATION OF

Module 1: Administrative Information and Prescribing

1.1 Table of Contents of the Submission Including

1.2 Documents Specific to Each Region (e.g., Application Forms, Prescribing Information)

Module 2: Common Technical Document Summaries 2.1 Common Technical Document Table of Contents (Modules 2–5)

2.2 CTD Introduction 2.3 Quality Overall Summary 2.4 Nonclinical Overview 2.5 Clinical Overview 2.6 Nonclinical Written and Tabulated Summaries Pharmacology

2.7 Clinical Summary Biopharmaceutical Studies and Associated Analytical

Methods Clinical Pharmacology Studies Clinical Efficacy

Clinical Safety Literature References Synopses of Individual Studies Module 3: Quality

3.1 Table of Contents of Module 3 3.2 Body of Data

3.3 Literature References Module 4: Nonclinical Study Reports 4.1 Table of Contents of Module 4 4.2 Study Reports

4.3 Literature References Module 5: Clinical Study Reports 5.1 Table of Contents of Module 5 5.2 Tabular Listing of All Clinical Studies 5.3 Clinical Study Reports

The CTD specifies many section headings and numbers This section provides answer to the following questions:

Could guidance be provided for all modules on headings in relation to document location and the section headings within those documents?

Could guidance also be provided on where in the CTD and eCTD multiple documents can be located in the hierarchy?

Could guidance be given on how documents should be paginated and on what the Table of Contents for each module should therefore include?

A document, for paper submission, is a set of pages that are numbered sequentially and separated from other documents by a tab, as described in the Document Pagination and Segregation section of this Annex In electronic submissions, a document can be equated to a file, and the granularity of paper and electronic submissions should be equivalent; however, when a paper submission is updated to become an electronic submission, some changes in granularity may be introduced to facilitate ongoing lifecycle management In an electronic submission, a new file starts at the same point where a tab divides documents in a paper submission.

When deciding whether one or more documents or files are appropriate, maintain consistency: once a specific approach is adopted, apply it throughout the life of the dossier The intent is to provide replacement documents or files whenever information changes, ensuring the dossier remains up to date and coherent.

These tables outline the levels in the CTD/eCTD hierarchy where documents or files should be positioned and indicate whether a single document or multiple documents are appropriate at each level They cover all sections of the CTD/eCTD, though, for individual submissions, not every section may be applicable.

Module 2 2.1 The TOC is only called for in the paper version of the CTD; there is no entry needed for the eCTD 2.2

Documents rolled up to this level are not considered appropriate

One document may be submitted at this level

Note 1: Optionality of granularity for the Quality Overall Summary is provided in order to accommodate different levels of complexity of products The applicant can choose the level at which the QOS is managed.

Note 2: One document should be submitted for each drug substance. Note 3: For a drug product supplied with reconstitution diluent(s), the information on the diluent(s) should be provided in a separate part “P” document.

Note 4: One document for each indication should be submitted, although closely related indications can be within a single document.

Module 3 Note 1 3.1 The TOC is only called for in the paper version of the CTD; there is no entry needed for the eCTD

3.3 One file per reference Note 6

Documents rolled up to this level are not considered appropriate

One or multiple documents can be submitted at this level

Note 1: In choosing the level of granularity for this module, the applicant should consider that, when relevant information is changed at any point in the product’s lifecycle, replacements of complete documents/files should be provided in the CTD and eCTD.

Note 2: For a drug product containing more than one drug substance, the information requested for part “S” should be provided in its entirety for each drug substance.

Note 3: For a drug product supplied with reconstitution diluent(s), the information on the diluent(s) should be provided in a separate part “P,” as appropriate.

Note 4: The lower level of headings included in CTD-Q at this point are unlikely to be individual documents or files.

Note 5: Refer to regional guidances.

Note 6: Literature references should be listed in the tables of contents.

Module 4 4.1 The TOC is only called for in the paper version of the CTD; there is no entry needed for the eCTD 4.2 4.2.1 4.2.1.1 Studies Note 1

4.2.1.2 Studies Note 1 4.2.1.3 Studies Note 1 4.2.1.4 Studies Note 1 4.2.2 4.2.2.1 Studies Note 1

4.2.2.2 Studies Note 1 4.2.2.3 Studies Note 1 4.2.2.4 Studies Note 1 4.2.2.5 Studies Note 1 4.2.2.6 Studies Note 1 4.2.2.7 Studies Note 1 4.2.3 4.2.3.1 Studies Note 1

4.2.3.4.2 Studies Note 1 4.2.3.4.3 Studies Note 1 4.2.3.5 4.2.3.5.1 Studies Note 1

4.2.3.5.2 Studies Note 1 4.2.3.5.3 Studies Note 1 4.2.3.5.4 Studies Note 1 4.2.3.6 Studies Note 1

4.2.3.7.3 Studies Note 1 4.2.3.7.4 Studies Note 1 4.2.3.7.5 Studies Note 1 4.2.3.7.6 Studies Note 1 4.2.3.7.7 Studies Note 1 4.3 One file per reference Note 2

Documents rolled up to this level are not considered appropriate One or multiple documents can be submitted at this level

Note 1: Typically, a single document should be provided for each study report included in Module 4 However, where the study report is large (e.g., a carcinogenicity study), the applicant can choose to submit the report as more than one document In this case, the text por- tion of the report should be one document and the appendices can be one or more documents In choosing the level of granularity for these reports, the applicant should consider that, when relevant information is changed at any point in the product’s lifecycle, replacements of complete documents/files should be provided.

Note 2: Literature references should be listed in the tables of contents.

Module 5 5.1 The TOC is only called for in the paper version of the

CTD; there is no entry needed for the eCTD 5.2

5.3.1.2 Studies Note 1 5.3.1.3 Studies Note 1 5.3.1.4 Studies Note 1

5.3.3.2 Studies Note 1 5.3.3.3 Studies Note 1 5.3.3.4 Studies Note 1 5.3.3.5 Studies Note 1

5.3.5.2 Studies Note 1 5.3.5.3 Studies Note 1 5.3.5.4 Studies Note 1 5.3.6

5.4 One file per reference Note 3

Documents rolled up to this level are not considered appropriate One document can be submitted at this level

One or multiple documents can be submitted at this level

Note 1: The applicants should ordinarily provide the study reports as multiple documents (a synopsis, a main body of the study report, and appropriate appendices) Appendices should be organized in accordance with the ICH E3 guideline, which describes the content and format of the clinical study report In choosing the level of granularity for reports the applicant should consider that, when relevant information is changed at any point in the product’s lifecycle, replacements of complete documents/files should be provided.

Note 2: For applications in support of more than one indication, this section should be repeated for each indication.

Note 3: Literature references should be listed in the tables of content.

Every document should be numbered starting at page one, except for individual literature references, where the existing journal page numbering is considered sufficient Applicants need not display the number as “1 of n,” where n is the total number of pages in the document Additionally, all pages of a document should include a unique header or footer that briefly identifies its subject matter In a paper-based drug submission, a similar identifier should be used on a tab that precedes the document, to facilitate finding that document within the dossier An abbreviation of the full section number and title can be used.

If a section contains more than one document, a specific

Table of Contents for that section can be included to identify the chronology and titles of the documents contained therein, for example,

• Table of Contents, listing the title of Procedure

If a section contains only a single document (e.g., 3.2.S.1.1

Nomenclature), only a tab identified by “3.2.S.1.1

Nomenclature” should precede the document.

In order to avoid fifth-, sixth-level subheading numbering (e.g., 2.6.6.3.2.1) within a document, the applicant can use a shortened numbering string In this case, the document number and the name (e.g., 2.6.6 Toxicology

To ensure clear document structure, place the written summary in the page headers or footers and apply hierarchical section numbering throughout the text, using examples like 1, 1.1, 2, 3, 3.1, 3.2, and so on The full numbering string, such as 2.6.6.3.2.1, is also acceptable for precise references This approach supports consistent table of contents formatting and easy navigation within the document.

The 2.1 CTD Table of Contents should go down to the third

(e.g., 2.3.S) or fourth (e.g., 2.3.S.1) level, depending on how a document is defined for the Quality Overall Summary (See

Definition of a Document for Module 2.)

Module 3 The Table of Contents provided under Section 3.1 should cover the high-level section numbering, the associated section heading, and the volume number in the order that they appear in the drug submission This Table of Contents would be used to identify the contents of Module 3 as defined in the M4Q guideline It should go down to the fifth level only (e.g., 3.2.P.2.1) Note that additional subsections and subheadings are defined in the M4Q guideline beyond this level (e.g., under 3.2.P.2) and this formatting should be used within the dossier, despite not being included in the 3.1 Table of Contents The lower level Table of Contents described under Document Pagination and Segregation should be excluded from the 3.1 Table of Contents.

At the applicant’s discretion, a Table of Contents may be added to a section that contains multiple documents to identify the chronology and the subject matter of each document If there is a need to introduce additional headers or subsection numbering beyond what is defined in the M4Q guideline, these elements should be created only within the document itself—not as a separate document or as a new subsection—and a specific Table of Contents for that document can be included to identify the chronology and titles of its subsections These documents and subsections should not appear in the 3.1 Table of Contents.

Furthermore, additional attachments or appendices should not be incorporated into this formatting, except as a document under a section where multiple documents might be provided

In the relevant section, include a cross-reference to any attached or appended document If you need to add additional information to a section that consists of a single document, incorporate that information within that document.

All Table of Contents title entries should correspond to the heading names and section numbering defined in the M4Q guideline or to the identifiers appearing on tabs (for a paper-based drug submission only), preferably by their full title so any abbreviated title used on the corresponding tab is easily identified The Table of Contents should not specify any page numbers.

Literature References should be listed in a Table of Contents specific for this section.

Module 4The Table of Contents for Module 4 should include all of the numerical items listed in the CTD guideline in order to identify all of the important components of the application (e.g., 4.2.3.5.1 Fertility and Early Embryonic Development) and should continue down to at least the level of the study report Thus, each study report should be identified in the table of contents The sections of a study report could be identified in the Module 4 Table of Contents of the dossier or only in the Table of Contents of the individual study report.

Illustration of part of the Module 4 Table of Contents

Study aa-aaa: 30 day repeat dose toxicity study with drug Cinrat

Study bb-bbb: 6 month repeat dose toxicity study with drug Cinrat

Study cc-ccc: 30 day repeat dose toxicity study with drug Cindog

Study dd-ddd: 6 month repeat dose toxicity study with drug Cindog

Study ee-eee: Ames test with drug C etc.

Quality

This document is intended to provide guidance on the format of a registration application for drug substances and their corresponding drug products as defined in the scope of the

ICH Guidelines Q 6A (“NCE”) and ICH Guideline Q 6B

The "Biotech" format may also be appropriate for certain other categories of products To determine the applicability of this format to a particular product, applicants should consult with the appropriate regulatory authorities.

Sections following the headings are intended for explanatory and illustrative purposes and should incorporate information described in existing ICH guidelines, though harmonized content may not be available for all sections; the “Body of Data” simply indicates where such information should appear within the document, and this guideline does not prescribe the exact type or extent of supporting data, since requirements may vary according to regional guidance.

Module 3.2.R (Regional Information) section titles illustrate topics that are not common to all ICH regions Therefore, the information provided in these sections should be based on the relevant regional guidelines.

3.1 TABLE OF CONTENTS OF MODULE 3

A Table of Contents for the filed application should be provided.

Information on the nomenclature of the drug substance should be provided For example,

• Other nonproprietary name(s), for example, national name, United States adopted name (USAN), Japanese accepted name (JAN), British approved name (BAN)

• Chemical abstracts service (CAS) registry number

The structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided.

The schematic amino acid sequence indicating glycosylation sites or other posttranslational modifications and relative molecular mass should be provided, as appropriate.

A list should provide physicochemical and other relevant properties of the drug substance, including biological activity for biotech.

3.2.S.2.1 Manufacturer(s) (Name, Manufacturer) The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

3.2.S.2.2 Description of Manufacturing Process and

Process Controls (Name, Manufacturer) The description of the drug substance manufacturing process demonstrates the applicant’s commitment to the reliable manufacture of the drug substance Information should be provided to adequately describe the manufacturing process and the process controls, including each manufacturing step, in-process controls, critical control points, and the methods used to ensure quality, safety, and regulatory compliance For example, the description should cover raw material specifications, process validation data, batch records, analytical testing, and stability data to confirm identity, purity, potency, and overall product quality.

Provide a comprehensive flow diagram of the synthetic process that includes molecular formulas, molecular weights, yield ranges, and the chemical structures of starting materials, intermediates, reagents, and the final drug substance, all reflecting stereochemistry, and clearly identify the operating conditions and solvents used at each step.

Submit a detailed, sequential procedural narrative of the manufacturing process that clearly maps the full workflow from start to finish The narrative must include representative quantities of raw materials, solvents, catalysts, and reagents reflecting the batch scale used in commercial manufacture, identify critical steps and decision points, and describe the necessary process controls, equipment, and operating conditions (such as temperature, pressure, pH, and time) to ensure reproducibility and product quality This focused summary provides the essential elements for production planning, quality assurance, and regulatory compliance.

Alternate processes should be explained and described with the same level of detail as the primary process, ensuring parity in documentation for quality control and regulatory compliance Reprocessing steps should be identified and justified, and any data supporting this justification should be referenced or filed in Section 3.2.S.2.5.

Information on the manufacturing process should be provided, starting with vial(s) of the cell bank and covering all major stages—cell culture, harvest, purification, and any required modification reactions—followed by filling, storage, and shipping conditions A clear, high-level overview supports quality assurance, regulatory compliance, and traceability across production lots while emphasizing critical parameters that influence cell viability and product consistency for safe distribution This end-to-end description ensures stakeholders understand the sequence from initial cell bank to final packaged product and outbound logistics, enabling scalable, compliant biopharmaceutical manufacturing.

Batch(es) and Scale Definition

An explanation of the batch numbering system, including information regarding any pooling of harvests or intermediates and batch size or scale should be provided.

Develop a flow diagram that illustrates the manufacturing route from the original inoculum (cells contained in one or more vials of the Working Cell Bank) up to the final harvesting operation The diagram should include all unit operations and intermediates, and provide relevant information for each stage such as population doubling levels, cell concentration, volumes, pH, cultivation times, holding times, and temperature It should identify critical steps and critical intermediates for which specifications are established (as described in Section 3.2.S.2.4) to ensure traceability, quality control, and regulatory compliance throughout the production process.

Describe each process step shown in the flow diagram, outlining how the step operates, its inputs and outputs, and how it connects with the other steps in the sequence Include the scale of operation, culture media and other additives (details provided in 3.2.S.2.3), and the major equipment required (details provided in the related sections), so the description supports accurate replication, regulatory compliance, and clear, keyword-rich content for search engine visibility.

Section 3.2.A.1); and process controls, including in-process tests and operational parameters, process steps, equipment, and intermediates with acceptance criteria (details provided in Section 3.2.S.2.4) Information on procedures used to transfer material between steps, equipment, areas, and buildings, as appropriate, and shipping and storage conditions should be provided (Details on shipping and storage provided in

Provide a flow diagram that illustrates the purification steps (unit operations) from crude harvests to the step immediately before filling the drug substance, ensuring that every purification stage is depicted and that all intermediates and relevant information for each stage are captured; the diagram should detail the sequence of unit operations, the materials at each step, the purification methods used, and any critical data such as yields, conditions, and outputs, enabling complete process understanding and traceability from harvest through pre-filling.

(e.g., volumes, pH, critical processing time, holding times, temperatures and elution profiles and selection of fraction, storage of intermediate, if applicable) should be included

Critical steps for which specifications are established as men- tioned in Section 3.2.S.2.4 should be identified.

Describe each process step identified in the flow diagram with detailed coverage of scale, buffers and other reagents (details in Section 3.2.S.2.3), major equipment (Section 3.2.A.1), and materials; for materials such as membranes and chromatography resins, include conditions of use and reuse supported by equipment details (Section 3.2.A.1) and validation studies for the reuse and regeneration of columns and membranes (Section 3.2.S.2.5); the description should also incorporate process controls, including in-process tests and operational parameters, with explicit acceptance criteria for each process step, for the equipment used, and for intermediates (Section 3.2.S.2.4).

Reprocessing procedures with criteria for reprocessing of any intermediate or the drug substance should be described

(Details should be given in Section 3.2.S.2.5.)

Information on the procedures used to transfer material between steps, equipment, areas, and buildings, as appropriate, along with the shipping and storage conditions, should be provided to ensure safe and efficient material handling The document should outline how transfers are conducted, who authorizes them, and the handling requirements for each stage and location, with detailed shipping and storage guidelines referenced in Section 3.2.S.2.4.

Filling, Storage, and Transportation (Shipping)

Provide a detailed description of the filling procedure for the drug substance, together with the full set of process controls, including in-process tests and critical operational parameters, and specify the acceptance criteria (details in Section 3.2.S.2.4) Also document the container closure system used for storage of the drug substance (details in Section 3.2.S.6) and outline the required storage and shipping conditions to ensure the drug substance’s integrity during handling and transport.

Nonclinical Study Reports

G eneral P rinciPleS of n onclinical o vervieW anD S ummarieS

This guideline provides recommendations for the harmo- nization of the Nonclinical Overview, Nonclinical Written

Summary, and Nonclinical Tabulated Summaries.

The primary purpose of the Nonclinical Written and

Tabulated summaries should provide a comprehensive, factual synopsis of nonclinical data, and the overview should interpret these findings, state their clinical relevance, and explicitly cross-link them with the quality attributes of the pharmaceutical The discussion should explain how nonclinical results translate into safe use and labeling implications, ensuring that risk assessment is supported and that quality considerations are integrated into the overall assessment of the product.

This guideline specifies an agreed format for organizing nonclinical reports in the Common Technical Document (CTD) for applications that will be submitted to Regulatory Authorities It is not intended to indicate which studies are required; it merely indicates an appropriate format for the nonclinical data that have been acquired.

The appropriate location for individual-animal data is in the study report or as an appendix to the study report.

4.1 TABLE OF CONTENTS OF MODULE 4

A Table of Contents should be provided that lists all of the nonclinical study reports and gives the location of each study report in the CTD.

4.2 STUDY REPORTS The study reports should be presented in the following order:

4.2.1 Pharmacology 4.2.1.1 Primary Pharmacodynamics 4.2.1.2 Secondary Pharmacodynamics 4.2.1.3 Safety Pharmacology

4.2.2.1 Analytical Methods And Validation Reports (if separate reports are available) 4.2.2.2 Absorption

4.2.2.3 Distribution 4.2.2.4 Metabolism 4.2.2.5 Excretion 4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)

4.2.3.1 Single-Dose Toxicity (in order by species, by route)

4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including supportive toxicokinetics evaluations) 4.2.3.3 Genotoxicity

4.2.3.3.1 In Vitro 4.2.3.3.2 In Vivo (including supportive toxicokinetics evaluations) 4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations)

4.2.3.4.1 Long-Term Studies (in order by species; including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics) 4.2.3.4.2 Short- or Medium-Term Studies

(including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics)4.2.3.4.3 Other Studies

(including range-finding studies and supportive toxicokinetics evaluations) (If modified study designs are used, the following subheadings should be modified accordingly)

Development (including mater- nal function)

4.2.3.5.4 Studies in Which the Offspring

(juvenile animals) Are Dosed and/or Further Evaluated

4.2.3.7 Other Toxicity Studies (if available)

4.2.3.7.3 Mechanistic Studies (if not included elsewhere) 4.2.3.7.4 Dependence

Tables and Figures for Written Summaries

The Nonclinical Tabulated Summaries Templates

Clinical Study Reports

Through the ICH process, a guideline on the structure and content of clinical study reports (E3) has been published This document provides guidance on organizing these study reports, the accompanying clinical data, and their references within a regulatory dossier.

CTD for registration of a pharmaceutical product for human use These elements should facilitate the preparation and review of a marketing application.

This guideline does not specify which studies are required for successful registration Instead, it provides guidance on the proper organization of clinical study reports within the application to support a clear, efficient regulatory review.

Detailed Organization of Clinical Study Reports and Related

The guideline prescribes a defined structure for placing clinical study reports and related information to streamline dossier preparation and review and to ensure completeness The placement of each report should reflect the study’s primary objective, and every study report should appear in only one section When a study has multiple objectives, it should be cross-referenced in the relevant sections If a section or subsection contains no report or information, an explicit note such as “not applicable” or “no study conducted” should be provided.

5.1 Table of Contents of Module 5

A Table of Contents for study reports should be provided.

5.1 Table of Contents of Module 5 5.2 Tabular Listing of All Clinical Studies 5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutical Studies 5.3.1.1 Bioavailability (BA) Study Reports 5.3.1.2 Comparative BA and BE Study Reports 5.3.1.3 In Vitro–In Vivo Correlation Study Reports 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

5.3.2.1 Plasma Protein Binding Study Reports 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

5.3.2.3 Reports of Studies Using Other Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports

5.3.3.2 Patient PK and Initial Tolerability Study Reports 5.3.3.3 Intrinsic Factor PK Study Reports

5.3.3.4 Extrinsic Factor PK Study Reports 5.3.3.5 Population PK Study Reports 5.3.4 Reports of Human Pharmacodynamic (PD) Studies

5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5.3.4.2 Patient PD and PK/PD Study Reports

5.3.5 Reports of Efficacy and Safety Studies 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies 5.3.5.3 Reports of Analyses of Data from More Than One Study

5.3.5.4 Other Clinical Study Reports 5.3.6 Reports of Postmarketing Experience 5.3.7 Case Report Forms and Individual Patient Listings

5.2 TABULAR LISTING OF ALL CLINICAL STUDIES

A tabular listing of all clinical studies and related information should be provided For each study, this tabular listing should generally include the type of information identified in Table

5.1 of this guideline Other information can be included in this table if the applicant considers it useful The sequence in which the studies are listed should follow the sequence described in Section 5.3 below Use of a different sequence should be noted and explained in an introduction to the tabular listing.

Bioavailability (BA) studies assess the rate and extent of release of the active substance from a medicinal product Comparative BA or bioequivalence (BE) studies may use pharmacokinetic (PK), pharmacodynamic (PD), clinical, or in vitro dissolution endpoints, and may be single-dose or multiple-dose investigations When the primary objective is to evaluate the drug’s PK but BA information is also collected, the study report should be submitted in Section 5.3.1 and referenced in Sections 5.3.1.1 and/or 5.3.1.2.

BA studies in this section should include

Pharmacokinetic studies compare the release and systemic availability of a drug substance from a solid oral dosage form with its systemic exposure when administered intravenously or as an oral liquid dosage form, providing critical insights into bioavailability and absorption for formulation development and regulatory assessment.

5.3.1.2 Comparative BA and BE Study Reports

Studies in this section assess how quickly and how much drug substance is released from similar dosage forms, such as tablet-to-tablet or tablet-to-capsule comparisons Comparative pharmacokinetic analyses, including BA (bioavailability) or BE (bioequivalence) studies, may encompass various formulation comparisons to determine equivalence or differences in release profiles.

• The drug product used in clinical studies supporting effectiveness and the to-be-marketed drug product

• The drug product used in clinical studies supporting effectiveness and the drug product used in stability batches

• Similar drug products from different manufacturers

5.3.1.3 In Vitro–In Vivo Correlation Study Reports

In vitro dissolution studies that provide BA information, including studies used in seeking to correlate in vitro data with in vivo correlations, should be placed in Section 5.3.1.3

Reports of in vitro dissolution tests used for batch quality control and/or batch release should be placed in the Quality section of the CTD.

5.3.1.4 Reports of Bioanalytical and Analytical

Bioanalytical and analytical methods used for biopharmaceutical studies or in vitro dissolution studies should ordinarily be documented in the corresponding individual study reports When a method is applied across multiple studies, its description and validation should be included once in Section 5.3.1.4 and then referenced in the relevant individual study reports.

5.3.2 r ePortS of S tuDieS P ertinent to

Human biomaterials refer to proteins, cells, tissues, and related materials sourced from humans that are used in vitro or ex vivo to evaluate the pharmacokinetic (PK) properties of drug substances Examples include cultured human colonic cells for assessing membrane permeability and transport processes, and human albumin for measuring plasma protein binding Of particular importance is the use of hepatocytes and hepatic microsomes to study metabolic pathways and to evaluate potential drug–drug interactions with these pathways Studies using biomaterials to address properties beyond PK, such as sterility or pharmacodynamics, should be reported in the Nonclinical Study Section (Module 4) rather than in the Clinical Study Reports Section.

5.3.2.1 Plasma Protein Binding Study Reports

Ex vivo protein binding study reports should be provided here Protein-binding data from PK blood and/or plasma studies should be provided in Section 5.3.3.

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies Reports of hepatic metabolism and metabolic drug interaction studies with hepatic tissue should be placed here.

5.3.2.3 Reports of Studies Using Other

Human Biomaterials Reports of studies with other biomaterials should be placed in this section.

5.3.3 r ePortS of h uman Pk S tuDieS

Pharmacokinetic (PK) assessments in healthy subjects and/or patients are essential for designing dosing strategies and titration steps, anticipating the effects of concomitant medications, and interpreting variations in pharmacodynamics (PD) Such PK analyses describe how the body handles a drug over time, focusing on peak plasma concentration (Cmax), total exposure (area under the curve, AUC), clearance, and the potential for accumulation of the parent drug and its active metabolite(s) By quantifying these parameters, researchers can optimize dosing regimens, predict drug–drug interactions, and understand PD differences across individuals Importantly, assessments should account for active metabolites that contribute to pharmacological activity, ensuring a comprehensive picture of overall efficacy and safety.

The PK studies whose reports should be included in Sections 5.3.3.1 and 5.3.3.2 are generally designed to (1) measure plasma drug and metabolite concentrations over time,

(2) measure drug and metabolite concentrations in urine or feces when useful or necessary, and/or (3) measure drug and metabolite binding to protein or red blood cells.

On occasion, PK studies may include measurement of drug distribution into other body tissues, body organs, or fluids

(e.g., synovial fluid or cerebrospinal fluid), and the results of these tissue distribution studies should be included in Section

5.3.3.1 to Section 5.3.3.2, as appropriate These studies should characterize the drug’s PK and provide information about the absorption, distribution, metabolism, and excretion of a drug and any active metabolites in healthy subjects and/or patients

Studies of mass balance and changes in PK related to dose

In pharmacokinetic (PK) studies, factors such as dose proportionality and time-dependent changes (for example, due to enzyme induction or antibody formation) are of particular interest and should be addressed in Sections 5.3.3.1 and 5.3.3.2 Beyond describing mean PK parameters in both healthy volunteers and patient populations, PK studies should also report the range of individual variability to characterize interindividual differences in drug exposure This approach is consistent with the ICH E5 guideline on Ethnic Factors in Drug Development, which calls for evaluation of potential ethnic differences in PK and drug response to inform dosing recommendations across diverse populations.

Factors that may lead to different drug responses across populations are categorized as intrinsic factors and extrinsic factors Intrinsic factors include age, gender, race, body weight and height, disease state, genetic polymorphisms, and organ dysfunction, which can alter pharmacokinetic processes and systemic exposure Extrinsic factors comprise drug–drug interactions, diet, smoking, and alcohol use, all of which can influence pharmacokinetics and exposure Studies examining how intrinsic and extrinsic factors affect systemic exposure should report their PK findings, with the results organized in Sections 5.3.3.3 and 5.3.3.4, respectively.

Beyond standard multi-sample pharmacokinetic (PK) studies, population pharmacokinetic (popPK) analyses that rely on sparse sampling in clinical settings can address how intrinsic factors (such as age, sex, and genetic makeup) and extrinsic factors (including concomitant medications, diet, and adherence) contribute to interindividual variability in drug exposure and dosing needs By modeling these covariates, population PK approaches quantify their impact on pharmacokinetic parameters, enabling more accurate dose optimization, improved therapeutic outcomes, and better labeling for personalized medicine even when rich sampling is not feasible.

PK-response relationship Because the methods used in population PK studies are substantially different from those used in standard PK studies, these studies should be placed in

5.3.3.1 Healthy Subject PK and Initial

Reports of PK and initial tolerability studies in healthy subjects should be placed in this section.

5.3.3.2 Patient PK and Initial Tolerability

Reports of PK and initial tolerability studies in patients should be placed in this section.

5.3.3.3 Intrinsic Factor PK Study Reports

Reports of PK studies to assess effects of intrinsic factors should be placed in this section.

5.3.3.4 Extrinsic Factor PK Study Reports

Reports of PK studies to assess the effects of extrinsic factors should be placed in this section.

Reports of population PK studies based on sparse samples obtained in clinical trials including efficacy and safety trials should be placed in this section.

According to CTD guidelines, the general properties of the drug substance, including physicochemical properties and biological activity, are listed in Section 3.2.S.1.3, but only for the form used in the drug product; more detailed information on the substance, including possible alternative forms such as polymorphs, belongs in Section 3.2.S.3.1 In manufacturing, all process controls belong to Section 3.2.S.2.2, with critical controls providing additional detail in Section 3.2.S.2.4 The discussion and justification of starting materials should be included in Section 3.2.S.2.3, and the analytical procedures for materials described in 3.2.S.2.3 should also be included there When a reagent used to produce the drug substance is manufactured via recombinant DNA technology and no new CTD headings can be added, the quality information for that reagent should be located in Section 3.2.S.2.3 (Control of Materials), including any applicable analytical procedures, to ensure proper traceability and compliance.

Analytical procedures for the control of materials, including starting materials, reagents, raw materials, and solvents, must be described in Section 3.2.S.2.3 (Control of Materials) For materials of biological origin, any adventitious agent safety evaluation, if applicable, should be covered in Section 3.2.A.2 The required information should reside in Section 3.2.S.2.3 under the Control of Materials heading Section 3.2.S.2.4 governs whether batch data for intermediates or other critical steps are included If release tests are performed on intermediates and at critical steps rather than on the drug substance, the corresponding analytical procedures and acceptance criteria should be presented in Section 3.2.S.4.

Batch data, together with the analytical procedures and acceptance criteria for intermediates or critical steps, should be presented in Section 3.2.S.2.4; acceptance criteria are referred to in Section 3.2.S.4.1, and the analytical procedures are referred to in Section 3.2.S.4.2 Process validation and/or evaluation are covered in Section 3.2.S.2.5 If justification for reprocessing is warranted by a regional authority, the information should be included as part of the description of the manufacturing process in Section 3.2.S.2.2 If there are critical controls associated with the reprocessing operation, these controls should be included in Section 3.2.S.2.4, and if validation information is warranted, it should be included in Section 3.2.S.2.5.

CTD Q Section 3.2 Issues/Questions Answers S.2.6 Manufacturing Pr ocess De velopment Should bioa vailability/bioequi valence study results that demonstrate product comparability follo wing process changes be described in Section 3.2.S.2.6?

Reports of bioavailability and bioequivalence studies that demonstrate comparability after formulation or process changes should be presented in Module 5, with cross-references to these reports placed in Section 3.2.S.2.6 for drug substance process changes, Section 3.2.P.2.2.1 for drug product formulation changes, or Section 3.2.P.2.3 for drug product process changes; a brief summary of the reports may be included in these sections when appropriate For S.3 Characterization, specifically S.3.1 Elucidation of Structure and Other Characteristics, studies conducted to determine the physicochemical characteristics of the drug substance should be included in that section.

Information on the studies conducted to determine the physicochemical characteristics of the drug substance should be included in Section 3.2.S.3.1, while Section 3.2.S.1.3 should provide only a list of the general properties of the drug substance For impurities, Section 3.2.S.3.2 should contain the structural characterization data and a summary of the methods used to prepare the impurities, i.e., the impurity synthesis or generation process.

Key information on impurity characterization should be included in Section 3.2.S.3.2, while the characterization of impurity reference standards belongs in Section 3.2.S.5, with additional guidance available in the Q&A under Section 3.3; critical questions to address include where chromatograms for impurities should be provided, where nonclinical and clinical data supporting impurity levels should be summarized, and whether data on impurities reported in batch analyses should appear in Section 3.2.S.3.2 or in Section 3.2.S.4.4.

According to ICH Q3A, chromatograms are part of analytical validation and relevant chromatograms should be included in Section 3.2.S.4.3, while the qualified level of each impurity, with cross-reference to supporting nonclinical and clinical studies, should be provided in Section 3.2.S.3.2 Data on observed impurities for relevant batches (clinical, nonclinical, stability) must be supplied in Section 3.2.S.3.2, regardless of whether the impurity is included in the specification, and this information can be cross-referenced to support other sections of the dossier as appropriate In Section 3.2.S.4.1, if there are different specifications for a drug substance from the manufacturer and/or applicant, they should be provided, and if alternative analytical procedures are used to control the drug substance, those procedures should also be listed in the specification (Section 3.2.S.4.1).

When appropriate, more than one specification should be included in Section 3.2.S.4.1, and any analytical procedure used to control the drug substance along with its associated acceptance criteria should be listed in the specification Section 3.2.S.4.2 Analytical Procedures recognizes that analytical procedures often change during the development of the drug substance; if these procedures are submitted to support the dossier, their placement should be clarified, and questions arise about whether an analytical procedure used only for stability studies belongs in Section 3.2.S.4.2 If the analytical methods for the drug substance and drug product are identical, can these methods and their corresponding validation, if applicable, be described in either Module 3.2.S or Module 3.2.P with a cross-reference (for example, a reference from 3.2.S to 3.2.P)?

Information on historical analytical procedures used to generate data included in batch analyses should be included in Section 3.2.S.4.4, and information on analytical procedures used solely for stability studies should be included in Section 3.2.S.7.3 Since sample preparation will differ, the analytical methods should appear in the relevant sections of Modules 3.2.S and 3.2.P In the Validation of Analytical Procedures (Section 3.2.S.4.3), chromatograms relevant to the validation should be included.

Per CTD Q Section 3.2, S.4.4 Batch Analyses, results from all relevant batches must be provided in the Batch Analyses section of the dossier to ensure complete batch-level data Any results from tests that are not listed in the specifications should also be provided, clearly identified as non-specified tests, and included with the batch data or in an addendum to the Batch Analyses section Collated data for a test evaluated across multiple batches should be presented as a single, consolidated dataset within the Batch Analyses section to enable direct cross-batch comparison.

Results from all relevant batches (clinical, nonclinical, and stability), including those used to justify acceptance criteria, should be provided in Section 3.2.S.4.4 If results come from tests not listed in the specification, they should be reported in Section 3.2.S.4 If data from batch analyses are collated and warranted, the data should be presented in Section 3.2.S.4.4 The justification of the specification is addressed in Section 3.2.S.4.5; if skip testing is considered appropriate, the justification should be included in Section 3.2.S.4.5 Rather than repeating information, a summary of data from other sections with a cross-reference to the detailed information should be provided to support the justification of the specification in the dossier.

To support the justification of the specification, a concise summary of data from other sections with cross-references to the detailed information can be provided Section S.5 covers Reference Standards or Materials, noting that reference standards might be available for the active moiety and impurities It is necessary to decide whether information on all reference standards should be included in Section 3.2.S.5 Additionally, guidance is needed on where characterization data for a reference standard should be placed within the CTD-Q.

Information warranted for a reference standard should be included in Section 3.2.S.5, and all characterization data for the reference standard should be included there, with cross-references to information in other sections (e.g., Section 3.2.S.3.2) included as appropriate to support traceability The document then addresses Section 3.2.S.6 on Container Closure System and Section 3.2.S.7 on Stability, including S.7.1 Stability Summary and Conclusions, S.7.2 Postapproval Stability Protocol and Stability Commitment, and S.7.3 Stability Data The guidance raises questions about whether stress studies should be located in Section 3.2.S.7.3, whether information on any changes in analytical procedures over the course of generating stability data should be included there, whether data from supporting studies can be included in Section 3.2.S.7.3, and whether information on analytical procedures unique to the stability program should be presented in Section 3.2.S.7.3.

Stress studies should be documented in Section 3.2.S.7.3, and the resulting data can be cited to validate analytical procedures where appropriate Section 3.2.S.7.3 should also include information on historical analytical procedures used to generate the stability data, along with data from supporting studies when relevant Additionally, any analytical procedures unique to the stability program should be described in Section 3.2.S.7.3.

CTD-Q Section 3.2.P.1 covers the Description and Composition of the Drug Product and raises key questions for regulatory submissions It asks where information on the composition of inks used on the drug product should be placed and where information on reconstitution diluents should be included It also asks whether an overfill should be indicated in Section 3.2.P.1 and whether information on the composition of the drug product beyond what is listed in the CTD-Q guideline can be included there.

Process Validation: General Principles and Practices

This FDA guidance presents the general principles and approaches FDA regards as appropriate elements of process validation for manufacturing human and animal drugs and biological products, including active pharmaceutical ingredients (APIs), which are collectively referred to in this guidance as drugs or products.

This guidance incorporates principles and approaches that manufacturers can use in validating a manufacturing process based on guidance principles listed in the references at the end of this chapter.

This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance

Adopting the lifecycle concept links product and process development with the qualification of the commercial manufacturing process and with maintaining the process in a state of control during routine commercial production This guidance promotes modern manufacturing principles, continuous process improvement, innovation, and sound science, and it applies to all drugs—human, veterinary, and biological—finished products and pharmaceutical and biological API, but it is not relevant for dietary supplements, medical devices, type A medicated articles, and human transplant tissues.

The guidance does not specifically address the validation of automated process control systems—such as computer hardware and software interfaces—that are commonly integrated into modern drug manufacturing equipment This topic is covered elsewhere in another chapter Nevertheless, the guidance remains relevant to validating processes that involve automated equipment in processing.

In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance enti- tled “Guideline on General Principles of Process Validation”

The 1987 guidance introduced substantial changes to the original concepts of validation and reflects FDA’s current thinking on process validation, aligned with the agency’s “Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach” initiative It emphasizes leveraging technological advances in pharmaceutical manufacturing and the adoption of modern risk management and quality system tools and concepts.

FDA has the authority and responsibility to inspect and evaluate process validation conducted by pharmaceutical manufacturers, and current good manufacturing practice (CGMP) regulations for validating drug manufacturing require that drug products be produced with a high degree of assurance that they meet all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)) Effective process validation is a cornerstone of drug quality, reinforcing the basic quality assurance principle that a drug should be fit for its intended use, an understanding that rests on ensuring consistent manufacturing performance and control of the conditions under which the product is produced.

• Quality, safety, and efficacy are designed or built into the product

• Quality cannot be adequately assured merely by in- process and finished-product inspection or testing

• Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications

Process validation, as defined in this chapter, is the systematic collection and evaluation of data from the process design stage through production, providing scientific evidence that a process is capable of consistently delivering quality products It encompasses a series of activities that occur across the entire lifecycle of the product and its process.

This guidance describes the process validation activities in three stages.

• Stage 1—Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities

• Stage 2—Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing

• Stage 3—Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control

This chapter describes activities typical in each stage, but in practice, some activities in different stages might overlap.

Before any batch is released for commercial distribution, a pharmaceutical manufacturer must establish a high level of confidence that the manufacturing process will consistently produce active pharmaceutical ingredients (APIs) and finished drug products that meet critical quality attributes—identity, strength, quality, purity, and potency This confidence should be supported by objective data from laboratory, pilot, and full-scale production studies, demonstrating robust process performance and control across scalable manufacturing steps.

Information and data must demonstrate that the commercial manufacturing process is capable of consistently producing products of acceptable quality under real-world manufacturing conditions, including those scenarios that pose a high risk of process failure Evidence should cover process performance across the manufacturing range, verify robustness to variations in materials, equipment, and environment, and show that quality attributes remain within predefined specifications This data‑driven validation supports confidence that the process can maintain product quality in both routine operations and challenging conditions.

A successful validation program depends upon information and knowledge from product and process development

This knowledge and understanding is the basis for establishing an approach to control that is appropriate for the manufacturing process Manufacturers should

• Understand the sources of variation,

• Detect the presence and degree of variation,

• Understand the impact of variation on the process and ultimately on product attributes, and

• Control the variation in a manner commensurate with the risk it represents to the process and product

Manufacturers must determine whether they have sufficient understanding of their manufacturing process to justify the commercial distribution of the product with a high degree of quality assurance Merely pursuing qualification without this understanding may not achieve adequate quality assurance Once the process is established and verified, it must be maintained in a state of control throughout its life cycle, even as materials, equipment, production environment, personnel, and manufacturing procedures change.

Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act, which states the following:

Under current good manufacturing practice (CGMP) standards, a drug is deemed adulterated if the methods, facilities, or controls used in its manufacture, processing, packing, or holding do not conform to CGMP or are not operated in accordance with CGMP This nonconformity can prevent the drug from meeting the safety requirements of the Act and from possessing the identity, strength, quality, and purity that it is represented to have.

FDA regulations describing CGMP are provided in 21 CFR parts 210 and 211.

Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and

Process validation rests on 21 CFR 211.100(a), which requires written procedures for production and process controls designed to ensure that drug products possess the identity, strength, quality, and purity they are represented to have The regulation obligates manufacturers to design a manufacturing process with defined operations and controls that reliably achieve these attributes, so product quality means consistent performance from batch to batch and unit to unit Many products are single-source or involve complex manufacturing steps, and validation provides assurance that the process is safeguarded against sources of variability that could affect output, potentially causing supply problems and jeopardizing public health.

Other CGMP regulations define the various aspects of validation Section 211.110(a), Sampling and testing of in-process materials and drug products, requires that control procedures

Regulatory guidance requires establishing controls to monitor output and validate the performance of manufacturing processes that could cause variability in the characteristics of in-process materials and the drug product This rule underscores that even well-designed processes must include in-process control procedures to ensure consistent final product quality.

CGMP regulations require batch samples to represent the batch under analysis and require that the sampling plan provide statistical confidence that the batch meets its predetermined specifications See § 211.160(b)(3) for representation and § 211.165(c) and (d) for the statistical confidence, with § 211.165(a) linking the results to the predefined specifications Section 211.110(b) offers two principles for establishing in-process specifications; the first principle states that in-process specifications for characteristics of in-process material and the drug product shall be consistent with the final drug product specifications.

Effective in-process material control is essential to ensure the final drug product consistently meets quality requirements The regulation’s second principle requires that in-process specifications be derived from previously observed acceptable process averages and their variability estimates whenever possible, and determined through appropriate statistical procedures where applicable This approach emphasizes that manufacturers must analyze process performance and actively control batch-to-batch variability to maintain product quality and regulatory compliance.

CGMP regulations define and govern activities related to process design, development, and maintenance Specifically, Section 211.180(e) requires that information and data on product performance and manufacturing experience be periodically reviewed to determine if changes to the established process are warranted Ongoing feedback about product performance is a fundamental aspect of process maintenance, helping ensure quality, compliance, and continuous improvement.

Bioequivalence Regulatory Compliance

Bioequivalence (BE) is defined in 21 CFR 320.1 as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study The FDA typically regards plasma drug concentration as a surrogate for the concentration at the site of action for systemically acting drugs 21 CFR 320.24 outlines the options for BE testing Therefore proving equivalence requires integrating multiple studies, including pharmacokinetic (PK) and pharmacodynamic (PD) assessments, controlled-clinical studies, in vitro studies, and any other specific model or study that may prove useful in establishing BE.

The concept of BE and the required proof by the regulatory agencies has evolved over the past several decades.

• In the United States, the 1902 federal law for biologics, particularly vaccines, required evaluation for

• The 1906 Food and Drugs Act added drugs other than biologics.

• The 1938 FDC act created FDA and evaluation of new drugs based on data in a filed NDA.

• The 1962 law added effectiveness requirement for the approval of NDA.

• 1960s, FDA permits marketing of “similars” while corresponding pioneer products undergo DESI reviews “Similars” came into market between 1938 and 1962.

• The 1970 FDA terminates marketing of “similars” unless

• DESI pioneer showed safety and efficacy, and

• “Similar” manufacturer submits aNDA with formulation and manufacture information (The Supreme Court in the United States v Generix

Drug Corporation supported FDA requirement for aNDA.)

• The 1984 generic law in the United States (Waxman-Hatch) created a generic approval system for all new drugs, including those approved after 1962 FDA finalized the bioequivalence (BA/BE) regulations (21 CFR 320) wherein the pioneer shows BA in NDA; “similars” to DESI- effective pioneers show BE leading to first U.S first generics Several revisions to 21 CFR 320 were made including the most recent one in April 2006 The Drug Price Competition and Patent Term Restoration Act of 1984 (Pub.L

The Hatch-Waxman Amendments created the current abbreviated new drug application (ANDA) framework under section 505(j) An ANDA, unlike a traditional NDA, does not require proof of the drug’s safety and effectiveness; instead it must demonstrate bioequivalence to the reference-listed drug (RLD) and rely on FDA’s finding that the RLD is safe and effective, reflecting the premise that bioequivalent products can be substituted for one another in most circumstances The Generic Animal Drug and Patent Term Restoration Act (GADPTRA), signed into law in 1988, allows sponsors to submit an abbreviated New Animal Drug Application (aNADA) for a generic version of any off-patent-approved animal drug, with certain exceptions noted in the law, regardless of whether the drug was approved prior to 1962.

National Research Council/Drug Effectiveness Study Implementation (NAS/NRC/DESI) review.

A generic drug is bioequivalent to the listed drug when the rate and extent of its absorption do not show a significant difference from the absorption of the listed drug This comparison is made when both are administered at the same molar dose of the therapeutic ingredient under similar experimental conditions, whether given as a single dose or multiple doses.

Bioequivalence testing in vivo and/or in vitro is required for most generic drug submissions, with the proposed product compared to the officially designated reference product Harmonized BE criteria for interchangeability include consideration of waivers for in vivo trials, since these studies are costly and may not always adequately discriminate for approval Worldwide BE requirements vary considerably, largely depending on regulators’ ability to enforce them, a situation shaped by economic and ethical considerations.

Drug regulatory authorities must ensure that all pharmaceutical products, including generic drugs, conform to the same standards of quality, efficacy, and safety as innovator products, and regulatory frameworks must adapt to diverse and emerging drugs and dosage forms that require bioequivalence demonstration, addressing BE issues for topical products, locally acting products, endogenous therapeutic proteins, and botanicals while establishing regulatory pathways and simultaneously streamlining evaluation and reducing costs for traditional dosage forms—especially in developing countries where cost pressures and the often weak correlation between in vivo data and clinical response prevail This chapter outlines these challenges and provides a pathway for prospective applicants seeking worldwide marketing approval.

The regulation of drug quality involves three arrange- ments in this country First, the U.S Congress gave the U.S

Pharmacopoeia and the National Formulary revision committees set the standards of strength, quality, and purity for drugs and their finished preparations; the FDA, authorized by the U.S Congress, establishes regulations governing the development and manufacture of safe and effective medicines.

Finally, in-house GMPs of the manufacturer, mostly dictated by the FDA regulations, ensure the quality of drug products

The FDA has established requirements for the bioavailability (BA) and bioequivalence (BE) of drug products All NDAs and amended NDAs must demonstrate in vivo BA of the drug product, followed by an in vitro dissolution test on individual batches to ensure product quality Table 1 compares regulatory filing requirements across different types of applications.

Applicants submitting an NDA or New Animal Drug

Under section 505(b) of the Federal Food, Drug, and Cosmetic Act, NDA and NADA submissions must document bioavailability (BA) in accordance with 21 CFR 320.21(a); if approved, an NDA drug product may later become the Reference Listed Drug (RLD) Under section 505(j), sponsors of an abbreviated NDA (aNDA) or abbreviated NADA (aNADA) must demonstrate pharmaceutical equivalence and then bioequivalence (BE) to be deemed therapeutically equivalent to the RLD BE is defined as relative BA and is established by comparing the performance of the test (generic) product to the reference (listed) product Pharmaceutical equivalents are drugs that share the same active ingredient, the same strength, the same dosage form and route of administration, and have comparable labeling while meeting compendia or other standards of identity, strength, quality, purity, and potency.

For an NDA, the active pharmaceutical ingredient (API) must be studied and controlled with specifications for polymorphic form, particle-size distribution, and other critical quality attributes that influence the quality of the resulting drug product Sponsors should, whenever possible and using compendial monographs where appropriate, align the API specifications with those deemed important for the Reference Listed Drug (RLD) When essential information is not available, applicants may rely on in vitro release testing to support batch-to-batch consistency FDA CMC guidances are generally applicable to ensure the identity, strength, quality, purity, and potency of the drug substance and the drug product for topical dermatological products.

According to FDA regulation 21 CFR 320.24, the preferred approaches to documenting bioequivalence (BE) are arranged in order of preference: first, pharmacokinetic (PK) measurements that quantify an active drug and/or its metabolites in blood, plasma, or urine; second, pharmacodynamic (PD) measurements; third, comparative clinical trials; and fourth, in vitro studies.

The science of bioequivalence (BE) is still evolving, with final rules emerging after years of debate and extensive validation of protocols The U.S FDA has finalized or drafted several BE guidelines, as summarized in Table 2.

III EQUIVALENCE DOCUMENTATION FOR MARKETING AUTHORIZATION

Pharmaceutically equivalent multisource pharmaceutical products must be verified to be therapeutically equivalent to one another to be considered interchangeable Several test methods are available to assess equivalence, including:

• Comparative BA (BE) studies, in which the active drug substance or one or more metabolites is mea- sured in an accessible biologic fluid such as plasma, blood or urine

TABLE 1 Data Requirement for Drug Approval In the United States

Application NDA NDA aNDA BLA

Preclinical Yes Yes/No No Yes

Clinical Yes Yes/No No Yes

CMC Yes Yes Yes (PE) Yes

PK & bioequivalence Yes Yes Yes

Labeling Yes Yes Yes Yes

Key regulatory abbreviations in pharmaceutical development include aNDA (abbreviated New Drug Application) and NDA (New Drug Application), which describe submission routes for new medicines; CMC (chemistry, manufacturing, and control) covers product quality, process validation, and manufacturing oversight; FD&C (Food, Drug, and Cosmetic Act) provides the legal framework for drug safety, labeling, and approvals; PHS (Public Health Service) influences biologics and public health considerations, while BLA (Biologic License Application) governs licensing for biologic products.

• Comparative PD studies in humans

• In vitro dissolution tests in combination with the

Biopharmaceutics Classification System (BCS, see below)

Regulatory acceptance of any test procedure used to establish equivalence between two pharmaceutical products depends on multiple factors, including the properties of the active drug substance and the finished drug product as well as the resources available to conduct the selected study When a drug attains meaningful concentrations in an accessible biological fluid such as plasma, bioequivalence studies are preferred; when it does not produce detectable levels in such fluids, comparative clinical trials or pharmacodynamic studies may be necessary to demonstrate equivalence In vitro testing, ideally supported by a documented in vitro–in vivo correlation or guided by biopharmaceutics classification system (BCS) considerations, can sometimes indicate equivalence between two products.

Regulatory authorities require in vivo bioequivalence documentation for multisource oral drug products when the product is compared to the reference pharmaceutical product All studies must be conducted using the formulation proposed for marketing For certain drugs and dosage forms, in vivo equivalence documentation—whether via a bioequivalence (BE) study, a comparative clinical pharmacodynamic (PD) study, or a comparative clinical trial—is considered especially important The factors for oral drug products that should be considered when requiring such in vivo equivalence documentation are

Immediate-release oral pharmaceutical products with systemic action when one or more of the following criteria apply.

1 Indicated for serious conditions requiring defi- nite therapeutic response.

2 Narrow therapeutic window/safety margin, steep dose-response curve.

3 PKs complicated by variable or incomplete absorption or absorption window, nonlinear PKs, pre-systemic elimination/high first-pass metabolism >70%.

4 Unfavorable physicochemical properties, e.g., low solubility, instability, metastable modifications, poor permeability.

5 Documented evidence of BA problems related to the drug or drugs of similar chemical structure or formulations.

6 Where there is a high ratio of excipients to active ingredients.

Nonoral and nonparenteral pharmaceutical products designed to act through systemic absorption (such as transdermal patches, suppositories):

Plasma concentration measurements over time (BE) are normally sufficient proof for efficacy and safety.

Sustained or otherwise modified-release pharmaceutical products designed to act through systemic absorption: Plasma concentration measurements over time (BE) are normally sufficient proof for efficacy and safety.

Fixed combination products (see WHO Technical Report Series No 825, 1992) with systemic action:

Final and Draft-Stage Biopharmaceutics Guidelines of the U.S FDA

Guideline Date Finalized/Draft Issued

Bioanalytical method validation-final 21 May 2018

Bioavailability and bioequivalence studies for orally administered drug products-general considerations

Cholestyramine powder in vitro bioequivalence-final 15 July 1993

Clozapine tablets: in vivo bioequivalence and in vitro dissolution testing-final 20 June 2005

Corticosteroids, dermatological (topical) in vivo-final 2 June 1999

Dissolution testing of immediate-release solid oral dosage forms-final 25 August 1997

Extended-release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations-final 26 September 1997

Metaproterenol sulfate and albuterol metered dose inhalers-final 27 June 1989

Statistical approach to establishing bioequivalence-final 2 February 2001

Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms on a biopharmaceutical classification system-final

Potassium chloride (slow-release tablets and capsules) in vivo bioequivalence and in vitro dissolution testing 6 June 1994

Food-effect bioavailability and fed bioequivalence studies December 2002

Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action-draft 3 April 2003

Plasma concentration measurements over time (BE) are normally sufficient proof for efficacy and safety.

EU Guidelines to Good Manufacturing Practice: Active Drug Substance

These guidelines provide essential guidance on good manufacturing practice (GMP) for the manufacture of active substances within a robust quality management system, aiming to ensure consistent compliance with quality and purity standards They are designed to help ensure that active substances meet the quality and purity requirements they claim or are represented to possess, supporting regulatory compliance and product safety.

Under these guidelines, “manufacturing” covers all operations from receipt of materials through production, packaging, repackaging, labeling and relabeling, quality control, release, storage, and distribution of active substances, along with the related controls The term “should” denotes recommendations that are expected to apply unless shown to be inapplicable, modified by any relevant annexes to the GMP guide, or replaced by an alternative approach demonstrated to provide at least an equivalent level of quality assurance.

Overall, the GMP guide does not cover personnel safety during manufacturing or environmental protection These controls are inherent responsibilities of the manufacturer and are governed by other parts of the legislation.

These guidelines do not define registration requirements or modify pharmacopoeial standards, nor do they affect the competent authority’s ability to establish specific registration requirements for active substances within the scope of marketing and manufacturing authorizations All commitments contained in registration documents must be met.

These guidelines govern the manufacture of active substances for medicinal products intended for both human and veterinary use They apply to the production of sterile active substances only up to the point immediately prior to the substance being rendered sterile The sterilization and aseptic processing of sterile active substances are not covered by these guidelines; however, such activities should be conducted in accordance with GMP as stipulated by Directive 2003/94/EC and interpreted in the GMP guide, including its Annex 1.

In the case of ectoparasiticides for veterinary use, other standards than these guidelines, that ensure that the material is of appropriate quality, may be used.

These guidelines exclude whole blood and plasma and align with Directive 2002/98/EC, which establishes the detailed requirements for the collection and testing of blood; however, the guidelines do include active substances that are produced using blood or plasma as raw materials They do not apply to bulk-packaged medicinal products They apply to all other active starting materials, subject to derogations described in the annexes to the GMP guide, in particular Annexes 2 to 7 where supplementary guidance for certain types of active substances may be found The annexes will be reviewed, but in the meantime, and only until this review is complete, manufacturers may continue to use Part I of the basic requirements and the relevant annexes for products covered by those annexes, or may already apply Part II.

Section 19 contains guidance that only applies to the manufacture of active substances used in the production of inves- tigational medicinal products, although it should be noted that its application in this case, though recommended, is not required by community legislation.

An active substance starting material is a raw material, intermediate, or an active substance used in the production of an active substance and incorporated as a significant structural fragment into the final molecule It can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house Active substance starting materials normally have defined chemical properties and a defined molecular structure.

Manufacturers must designate and document the rationale for the point at which active substance production begins; in synthetic processes, this point is defined as when active substance starting materials enter the process, while for other processes such as fermentation, extraction, and purification, the initiation point should be established on a case-by-case basis Table 6.1 guides the typical point of introduction for active substance starting materials From that point forward, the applicable GMP requirements must be applied to all intermediate and active-substance manufacturing steps, including the validation of critical process steps that impact the quality of the active substance.

Choosing to validate a process step does not automatically render that step critical; the guidance in this document is normally applied to the steps highlighted in gray in Table 6.1.

It does not imply that all steps shown should be completed

GMP stringency for active substance manufacturing should progressively increase as the process advances from early stages through purification and final packaging, ensuring quality and compliance at every step Physical processing of active substances—such as granulation, coating, or particle-size manipulation (including milling and micronizing)—must meet at least the standards set forth in these guidelines These guidelines, however, do not apply to steps that occur before the first introduction of the defined active substance starting material.

In the remainder of this guideline, the term active pharmaceutical ingredient (API) is used repeatedly and should be considered interchangeable with the term “active substance.”

The glossary in Section 20 of Part II is applicable only within Part II, and its terms should be interpreted strictly in the Part II context Some terms are already defined in Part I of the GMP guide and should be applied exclusively in the Part I context.

2.10 Quality should be the responsibility of all persons involved in manufacturing.

2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

2.12 The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity All quality-related activities should be defined and documented. 2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. 2.14 The persons authorized to release intermediates and APIs should be specified.

2.15 All quality-related activities should be recorded at the time they are performed.

2.16 Any deviation from established procedures should be documented and explained Critical deviations should be investigated, and the investigation and its conclusions should be documented.

2.17 No materials should be released or used before the sat- isfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine as described in section 10.20 or the use of raw materials or intermediates pending completion of evaluation).

2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects, and related actions (e.g., quality-related complaints, recalls, regulatory actions, etc.).

Application of This Guide to API Manufacturing

Type of manufacturing Application of this guide to steps (shown in gray) used in this type of manufacturing

Chemical manufacturing Production of the API starting material

Introduction of the API starting material into process

Physical processing and packaging API derived from animal sources

Collection of organ, fluid, or tissue

Cutting, mixing, and/or initial processing

Introduction of the API starting material into process

Physical processing and packaging API extracted from plant sources

Collection of plant Cutting and initial extraction(s) Introduction of the

API starting material into process

Physical processing and packaging Herbal extracts used as

Collection of plants Cutting and initial extraction Further extraction

Physical processing and packaging API consisting of comminuted or powdered herbs

Collection of plants and/or cultivation and harvesting

Cutting/comminuting Physical processing and packaging Biotechnology: fermentation/cell culture

Establishment of master cell bank and working cell bank

Maintenance of working cell bank

Cell culture and/or fermentation

“Classical” fermentation to produce an API

Maintenance of the cell bank Introduction of the cells into fermentation

2.2 r esPonsibiliTies of The q uAliTy u niT ( s )

2.20 The quality unit(s) should be involved in all quality- related matters.

2.21 The quality unit(s) should review and approve all appropriate quality-related documents.

2.22 The main responsibilities of the independent quality unit(s) should not be delegated These responsibilities should be described in writing and should include but not necessarily be limited to releasing or rejecting all APIs; releasing or rejecting intermediates for use outside the control of the manufacturing company; establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials; reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution; making sure that critical deviations are investigated and resolved; approving all specifications and master production instructions; approving all procedures impacting the quality of intermediates or APIs; making sure that internal audits (self-inspections) are performed; approving intermediate and API contract manufacturers; approving changes that potentially impact intermediate or API quality; reviewing and approving validation protocols and reports; making sure that quality-related complaints are investigated and resolved; making sure that effective systems are used for maintaining and calibrating critical equipment; making sure that materials are appropriately tested and the results are reported; making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/ or intermediates where appropriate; and performing product quality reviews (as defined in section 2.5).

Tiêu đề	Handbook of Pharmaceutical Manufacturing Formulations Volume Two, Uncompressed Solid Products
Tác giả	Sarfaraz K. Niazi
Trường học	Taylor & Francis Group
Chuyên ngành	Pharmaceutical Manufacturing
Thể loại	Book
Năm xuất bản	2020
Thành phố	Boca Raton

Định dạng
Số trang	457
Dung lượng	9,82 MB