Quality documentation in the CTD
The quality part of a dossier describes a medicine's active substance and finished product: what they are, how they are made and controlled, how they are packaged and how long they remain stable. How much manufacturing detail it carries also decides how freely the product can be changed after approval.
Module 3 and the information it holds
All the chemical, pharmaceutical and biological information about a product goes in Module 3 of the dossier, which is divided into two main parts, one on the active substance and one on the drug product. Guidelines specific to certain dosage forms should also be taken into consideration, such as those on modified-release oral and transdermal products, dry powder inhalers, pressurised metered-dose inhalation products and specifications for biotechnological and biological products.
In the United States, a company developing a new drug must submit, in an investigational new drug application (IND), sufficient information to assure "the proper identification, quality, purity, and strength" of the product (21 CFR 312.23). The chemistry, manufacturing and controls (CMC) group plans, drives and oversees the studies and experiments that generate the information needed to write the quality sections of the IND. For a biologic, the process is the product: the manufacturing process is as much a part of a company's licence as the final drug product.
The active substance
The Common Technical Document guidelines on what information to include in the active substance part, and in what degree of detail, should be followed. The relevant details of the active substance can be presented in full in the dossier, as a European Drug Master File or as a Certificate of Suitability from the active substance manufacturer. Details of the processing and testing of the substance, obtained from the manufacturer, should always be included.
General information
The general information gives the nomenclature of the active substance under the relevant headings:
- recommended INN
- pharmacopoeial name
- chemical name
- company or laboratory code
- other non-proprietary names
- Chemical Abstracts Service Registry number
- diagram of the structure
- molecular formula
- relative molecular mass
- physicochemical properties, such as solubility
It should also give short statements on the chemistry of the active substance molecule, covering such areas as chirality and polymorphism.
Manufacture
The manufacture section should have:
- the name, address and role of the manufacturer, preferably with contact phone numbers and email addresses
- a manufacturing flow diagram that shows the process step by step, using the chemical structures of the materials
- a description of the manufacturing process: each stage, the materials, the equipment and process parameters such as temperature, pH and times
- reprocessing details, if reprocessing occurs
- any controls used during the manufacturing process
- information on raw materials
A simple way to construct the flow diagram is to link the starting material, the intermediates and the finished active substance with a series of process arrows, around which the additional raw materials, solvents, catalysts and reagents should be listed with any relevant process parameters.
Material amounts and yield ranges of the end product should be stated for each step, for a standard commercial production batch size, and the batch size should always be stated. They can be given as a summary table or as text in the description of the process. In-process controls are tests that demonstrate control of the process at its various stages, and their methods and limits should be specified, with how samples are selected in quantity and location.
Information on the materials used in the manufacturing process must be given, including their function, the points at which they are used and the quality standards they comply with, such as the European Pharmacopoeia. The materials may include:
- starting materials
- solvents
- catalysts
- reagents
- auxiliary materials
This information is best presented as a table, and a specification should also be given for each material, with its limits and details of its test methods. Certification is also required as evidence that no materials with a risk of transmitting TSE or BSE are included in the manufacture of the drug substance. The intermediate products made during manufacture should also be adequately controlled, and the specification with the limits that control every intermediate should be presented as a table, with a written description of the methods.
The development of the manufacturing process should be discussed, covering changes to the process parameters, equipment, manufacturing site or scale: the changes made, the reasons for them and any consequences they had for the finished active substance.
Validation data and batch analyses
Validation data can be presented in a table that clearly states the results obtained and the relevant acceptance limits. At least two, and ideally three, example batches tested to the active substance specification should be given, with their batch histories as tables that include:
- batch numbers
- date of manufacture
- site of manufacture
- batch size
- source of drug substance used
The batch analysis data are best presented in a table, directly followed by the certificates of analysis.
Pharmaceutical development of the drug product
Formulations and test results can be presented as tables. Besides the active substance, the dosage form raises critical issues of product performance that should be addressed. For low-dose solid products, data should be provided on dissolution and content uniformity, and for multiple-dose liquid or semi-solid products, data on preservative efficacy tests. Critical parameters such as pH, dissolution, particle size distribution or rheology should be identified, with supporting data that show their influence and the suitability of the process controls that ensure the consistent manufacture of a well-controlled product.
The development of the manufacturing process should be justified, for example the selection of the process, the need to include certain excipients in different phases, the choice of equipment and the process parameters. This matters particularly for sterilised products, whose chosen method must be described and justified.
In most cases the process that makes a product's first batches, which are used in clinical trials, differs from the process that will make the pilot or commercial-scale batches. So the applicant should discuss every difference between the process for the clinical batches and the process proposed in the application for commercial batches, and whether each difference influences product performance; for a tablet, for example, a change in the process may affect hardness or dissolution, and so the release of the active substance from the dosage form.
The suitability of the container closure system should be discussed: the choice of construction material, any environmental protection issues and its compatibility with the drug product. Any performance issue, such as whether an inhaler delivers the required dose, should be included. The microbiological attributes of the drug product, and its compatibility with any reconstitution diluents or dosage devices, should not be ignored.
For a generic product claiming essential similarity, it is important to provide evidence of it through comparative dissolution, assay and impurity profiles of both the proposed and the reference products, and it is good practice to include at least two batches of the proposed product.
Excipients
The excipients section should provide:
- a list of the excipients in the formulation, with details of the quality standards to which they are controlled
- the analytical test methods used, including validation for any complex methods
- certificates of analysis for each excipient
- documentation of compliance with the regulatory requirements on TSE and BSE
Excipients are mainly controlled to pharmacopoeial standards, which can be referenced in a table. For a non-pharmacopoeial excipient, the specification should be given, stating its tests, their limits and the validation of complex methods. The TSE and BSE documentation can be formal statements from the material manufacturer of compliance with the relevant guidelines. A novel excipient should be given full details in the format of the active substance section, with references to supporting safety data. For water, details of its manufacture, even when it is produced on site, and of its quality controls should be provided.
The drug product specification
The final specification the product complies with at release and during its shelf life should be presented as a table, each test with its limit. The general specification would usually include:
- a visual description of the product
- two specific identity tests for the active substance or substances
- assay of the active substance or substances
- related substances
- microbial quality
- identification tests for all colouring agents used in the product
Product-specific tests are included for different products, such as:
- for solid oral dosage forms, uniformity of content for an active substance under 2 mg or 2% w/w or for low-dose products, a dissolution test, and a disintegration test, which is not required if a dissolution test is included
- for dispersible tablets, a dispersion test
- for parenteral products, a particulate matter test and a sterility test
- for ophthalmic suspensions or ointments, a particle size test
- for pressurised inhalers, a test of the deposition of the emitted dose and a test of the number of deliveries per container
The tests and limits in the product specification should be justified, with a brief explanation of why each test is included and how its limit was set.
Analytical procedures and their validation
The analytical procedure for each test should be supplied in enough detail for the method to be replicated, including reagents with their quantities, equipment and test parameters. As far as possible, the tests should comply with the European Pharmacopoeia or other relevant pharmacopoeias. Complex non-pharmacopoeial methods should be suitably validated as the guidelines on analytical method validation detail, and the validation details can include:
- specificity: whether the method picks up the specific substance
- linearity and range: the range of concentrations over which the method works as it is expected to
- accuracy: whether the method is accurate
- precision: whether the method is precise, repeatable and reproducible, for example whether a change of analyst affects the results
- detection limit: the level at which impurities can be detected
- quantitation limit: the level at which impurities can be measured
- robustness: which changes in the method change the results obtained
Analytical test method validation should be provided for each test performed on the product the application is made for. Microbiological testing of the product should be provided with its validation data, in compliance with the requirements of the European Pharmacopoeia.
Batch analyses and impurities
The drug product specification should be supported by the results of ideally three batches tested to it, with their batch numbers, date of manufacture, batch size and test results, best presented in a table together with the certificates of analysis. The potential impurities in the product should be described in sufficient detail, with their structures, their chemical names and a brief discussion of their route of formation. Where the manufacturing process can be shown to generate no additional impurities, the characterisation of impurities in the active substance section can be referenced.
Reference standards
The reference standards section of both the active substance and the drug product parts should provide:
- certificates of analysis of the reference standards and working standards
- a discussion of how the standards are obtained, generated or standardised
Where the drug product's standards are the same as those used for the active substance, the drug product part can refer to the reference standards in the active substance section.
Container closure
The container closure section of both the active substance and the drug product parts should provide:
- a full description of the container closure system, primary and any secondary packaging
- the material of construction
- drawings where relevant
- specifications
- details of the test methods
- certificates of analysis from the active substance manufacturer and the packaging material manufacturer
- compliance with the relevant pharmacopoeia monograph or with EC legislation on contact with foodstuffs, for example for plastic materials
For the drug product, the section should also provide data on migration and extraction studies performed for semi-solids and liquids in plastic primary packaging. For the active substance, it should comment on the compatibility of the packaging materials with the substance, covering the possibility of sorption, extractables and leaching. Some medicinal products, such as paracetamol-containing products in the UK, also require certification of compliance with the Medicines Regulations on Child Safety.
Stability
The stability section should provide:
- batch histories of the stability batches
- the type of packaging and the pack sizes used
- the conditions for long-term and accelerated storage
- the stability protocol and the duration of the stability study
- the characteristics studied
- the proposed shelf life and the recommended storage temperature
Appendices and regional information
The dossier has an appendix section that covers facilities and equipment for biotechnological products, the adventitious agents safety evaluation, which assesses the risk of potential contamination, and novel excipients.
The regional information section should include the supporting documents for Module 3:
- the process validation protocol
- details of any medical device used in the product
- certificates of suitability
- certification of compliance with the requirements on materials of animal or human origin contained in the product or used in its manufacturing process
How much detail an application commits the sponsor to
Too much detail in a submission can make post-approval changes a nightmare, and too little can lead to refusal of the application. Every submission has its own required level of detail, and the considerations in deciding it for a new drug application (NDA) include:
- the items discussed in presubmission meetings with the US Food and Drug Administration (FDA): the submission should cover any points the FDA manager discussed in meetings for the IND, the NDA or the biologics license application (BLA)
- which modules are regulatorily binding: a change to such a module requires a post-approval submission, so too much detail in them can adversely affect the ability to make post-approval changes to the product
- a relationship with the FDA manager for the project, which can help with making submissions geared toward the FDA reviewer
- comparability protocols
The right level of detail depends on the complexity of the product, and the more complex the product, the more detail is needed. Small-molecule drug products are better known and usually need less detail than large-molecule products such as vaccines, biologics, and gene and cell therapy products.
ICH Q12 (January 2020), in its Appendix 1, gives examples of the typical regulatorily binding content of Module 3 of the electronic Common Technical Document (eCTD), the established conditions. Every post-approval change in manufacturing must be reviewed by someone in CMC regulatory affairs to determine whether it changes the established conditions in the existing applications.
Biologics and vaccines
Biologics pose particular issues: they are grown and harvested rather than synthesised, they are exponentially larger than small molecules, which makes them harder to identify, characterise and isolate, and their susceptibility to contamination presents regulatory challenges. Large-molecule applications need more detail, and they can be as much as twice as long as small-molecule applications. A biologic application can need more regulatory detail in Module 2.3, the quality overall summary, and in some parts of Module 3. Contamination and stability are very important to consider, and process validation is a requirement for a BLA. A level of redundancy between Modules 2 and 3 can be required for large molecules, and the Module 3.2.A appendices show how effective the aseptic quality controls are. The regulation of vaccines has content requirements similar to a BLA's.
Comparability protocols and drug master files
A comparability protocol is a comprehensive written plan to assess the effect of potential or known changes to be made after approval. It may be submitted as part of the original application or as a post-approval change. It helps the applicant know which studies and tests a post-approval change will need, and it can help with post-approval submissions by giving an agreed list of what will be needed and what the submission will have to contain, and may even reduce their regulatory burden.
When there are two or more manufacturing partners, a drug master file (DMF) allows each to protect its intellectual property. The DMF holder files the DMF with the FDA and includes a letter of authorization in it, or amends an existing DMF with one, so that the partner submitting the NDA or supplemental NDA can reference the information in the DMF. There are four types of DMF:
- Type 2: drug substance, drug substance intermediate and material used in their preparation, or drug product
- Type 3: packaging material
- Type 4: excipient, colorant, flavor, essence or material used in their preparation
- Type 5: FDA-accepted reference information
Country-specific CMC dossiers from one master dossier
Preparing multiple country-specific CMC dossiers to support clinical trials worldwide can be a long process because of the authoring, review and audit cycles. Treating each country's dossier as an individual document, a so-called nose-to-tail approach, can delay the start of clinical trials in many countries. One streamlined approach eliminates the need for multiple cycles by using a single master dossier, which includes the information needed for all countries, to prepare the country-specific versions. It reduced preparation time from approximately four years to about six weeks, and it reduced auditing resources by 90% while maintaining the 100% data auditing standard. More than 150 CMC dossiers had been prepared with it since 2010.