Guidance for industry: Preparation of veterinary new drug submissions and abbreviated new drug submissions (new and generic drugs) - Quality requirements: Appendices

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• Appendix 1: Definitions
• Appendix 2: Index for Part 2: Requirements for manufacturing and quality control

Appendix 1: Definitions

Adventitious agent: contaminating microorganism of the cell culture or starting/raw materials, including bacteria, fungi, mollicutes (mycoplasmas or spiroplasmas), mycobacteria, rickettsia, protozoa, parasites, agents causing TSEs and viruses that have been unintentionally introduced into the manufacturing process of a biological product. The source of the contaminant may be the legacy of the cell line, the raw materials used in the culture medium to propagate the cells (in banking, in production or in their legacy), the environment, personnel, equipment or elsewhere.

Aqueous solution: A solution with water as the predominant solvent. Dosage forms characterized as solutions are normally classified by their route of administration (e.g. oral, dermatological, ophthalmic, otic, nasal, inhalation, injection).

Batch: A quantity of drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, produced according to a single production order and as attested by the signatories to the order. In the case of continuous manufacture, a batch corresponds to a defined fraction of the production that is characterized by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.

Certificate of suitability (CEP): A certificate of compliance of a drug substance with the relevant requirements of the European Pharmacopoeia monographs for use in medicinal products issued by the European Directorate for the Quality of Medicine of the Council of Europe (EDQM).

Container closure system (CCS): The sum of packaging components that together, contain and protect either the drug substance or drug product. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection.A packaging system is equivalent to a CCS.

Continuous process verification (CPV): An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8).

Control strategy: A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Critical dose drug: Drugs where comparatively small differences in dose or concentration lead to dose‐ and concentration‐dependent serious therapeutic failures and/or serious adverse drug reactions which may be persistent, irreversible, slowly reversible, or life threatening.

Critical (manufacturing) step: A manufacturing process/step that may result in a potential change in the purity/impurity profile or due to the nature of the starting materials or resulting product/intermediate, requires containment within a specially designed manufacturing area or production facility, for example, the development and preparation of cell banks and seed lots, initial propagation, scale-up, blood and plasma pooling and fractionation, fermentation, harvesting, inactivation, purification, addition of adjuvants or preservatives, the conjugation and pooling of bulk concentrates and the final preparation of drug product including concentration/diafiltration, formulation, sterile filtration, filling and lyophilization.

Critical process parameter: A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Critical quality attribute (CQA): A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Design space: The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the sponsor and is subject to regulatory assessment and approval.

Dissolution testing (in vitro quality control): A dissolution test procedure identified in the pharmacopoeia for routine quality control of product batches, generally a one time-point dissolution test for immediate release products and a three or more time-points dissolution test for modified release products.

Dose/solubility volume (DSV): The highest therapeutic dose (milligrams) divided by the solubility of the substance [milligram/millilitres (mg/mL)] at a given pH and temperature. For example, if a drug substance has a solubility of 31 mg/mL at pH 4.5 (37 °C) and the highest dose is 500 mg, then the DSV = 500 mg/ 31mg/mL = 16 mL at pH 4.5 (37 °C).

F0 (i.e. the Lethality Factor) : the amount of time in minutes, equivalent to time at 121 °C, to which a unit has been exposed during a sterilization process.

Facility: A building in which a specific manufacturing operation or multiple operations take place.

Functional secondary packaging: Packaging material not in direct contact with the product that provide additional protection or serve to deliver the product (e.g. injector pen/device).

Hydrate: A compound that contains water within its crystal structure.

Immediate release dosage forms: Dosage forms that allow the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.

In-process control: Check performed during production in order to monitor and, if necessary, to adjust the process to ensure that the finished product conforms to its specifications. The control of the production environment or equipment may also be regarded as part of in-process control.

In-use period: The time period during which a drug product or drug substance is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label.

Isomers: Compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms in space (e.g. structural isomers, stereoisomers).

Medicated feed: A mixed feed that contains a medicating ingredient [1.(1) of the Feeds Regulations, 2024].

Medicated premix (or drug premix): A drug for veterinary use to which a drug identification number (DIN) has been assigned, where the directions on its label specify that it is to be mixed with feed as defined in section 1 of the Feeds Act. (C.01A.001 of the FDR). It is a veterinary drug product prepared in advance with a view to the subsequent manufacture of medicated feeds.

Modified release dosage forms: Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release dosage forms include both delayed and extended release drug products.

Normal Operating Range (NOR): The range in which unintentional variation is reasonably anticipated to occur during operation for a process parameter when it is set at its target value.

Pharmaceutical equivalent: a new drug that, in comparison with another drug, contains identical amounts of the identical medicinal ingredients, in comparable dosage forms, but that does not necessarily contain the same non-medicinal ingredients (C.08.001.1 in the FDR).

Pilot scale: A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. The pilot batch size should correspond to at least 10% of the production scale batch, i.e. such that the multiplication factor for the scale-up does not exceed 10. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.

Polymorph: A different crystalline or amorphous forms of the same drug substance. This may include solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms.

Primary container closure system component: Packaging material in direct contact with the product.

Proven Acceptable Range (PAR): A characterised range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria.

Quality by Design (QbD): A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

Quality Target Product Profile (QTPP): A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Release controlling excipient (or agent): An excipient in the final dosage form whose primary function is to modify the duration of release of the active drug substance from the dosage form.

Reprocessing: Introducing an intermediate or drug substance, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g. distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.

Reworking: Subjecting an intermediate or drug substance that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or drug substance (e.g. recrystallizing with a different solvent).

Salt: A compound formed by the ionic interaction of the ionized form of an acid or a base with a counter ion.

Schedule B pharmacopoeia: Pharmacopoeia listed in Schedule B of the Food and Drugs Act (e.g. United States Pharmacopeia, European Pharmacopoeia).

Solution: Liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents.

Solvate: A compound which during the crystallization process traps a fixed molar ratio of solvent molecules in the crystal structure. The solvent may be highly bound in the crystal, or it may be more loosely bound in channels within the crystal.

Starting material: A starting material is a raw material, intermediate, or a drug substance that is used in the production of a drug substance and that is incorporated as a significant structural fragment into the structure of the drug substance.

Validation: The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment.

Appendix 2: Index for Part 2: Requirements for manufacturing and quality control

The following index outlines the folder structure for Part 2: Requirements for manufacturing and quality control for an NDS or ANDS that aligns with this guidance document. For the fulsome NDS or ANDS index, refer to the electronic zip folder structure for filing submissions.

• 2.S Drug substance
  • 2.S.1 General information
    • 2.S.1.1 Nomenclature
    • 2.S.1.2 Structure
    • 2.S.1.3 General properties
  • 2.S.2 Manufacture
    • 2.S.2.1 Manufacturer(s)
    • 2.S.2.2 Description of manufacturing process and process controls
    • 2.S.2.3 Control of materials
    • 2.S.2.4 Controls of critical steps and isolated intermediates
    • 2.S.2.5 Process validation and/or evaluation
    • 2.S.2.6 Manufacturing process development
  • 2.S.3 Characterization
    • 2.S.3.1 Elucidation of structure and other characteristics
    • 2.S.3.2 Impurities
  • 2.S.4 Control of drug substance
    • 2.S.4.1 Specification
    • 2.S.4.2 Analytical procedures
    • 2.S.4.3 Validation of analytical procedures
    • 2.S.4.4 Batch analyses
    • 2.S.4.5 Justification of specification
    • 2.S.5 Reference standards
  • 2.S.6 Container closure system
  • 2.S.7 Stability
    • 2.S.7.1 Stability summary and conclusions
    • 2.S.7.2 Post-approval stability protocol and stability commitment
    • 2.S.7.3 Stability data
• 2.P Drug product
  • 2.P.1 Description and composition of drug product
  • 2.P.2 Pharmaceutical development
    • 2.P.2.1 Components of drug product
    • 2.P.2.2 Drug product
    • 2.P.2.3 Manufacturing process development
    • 2.P.2.4 Container closure system
    • 2.P.2.5 Microbiological attributes
    • 2.P.2.6 Compatibility
  • 2.P.3 Manufacture
    • 2.P.3.1 Manufacturer(s)
    • 2.P.3.2 Batch formula
    • 2.P.3.3 Description of manufacturing process and process controls
    • 2.P.3.4 Controls of critical steps and intermediates
    • 2.P.3.5 Process validation and/or evaluation
  • 2.P.4 Control of excipients
    • 2.P.4.1 Specifications
    • 2.P.4.2 Analytical procedures
    • 2.P.4.3 Validation of analytical procedures
    • 2.P.4.4 Batch analyses
    • 2.P.4.5 Characterization of impurities
    • 2.P.4.6 Novel excipients
  • 2.P.5 Control of drug product
    • 2.P.5.1 Specification(s)
    • 2.P.5.2 Analytical procedures
    • 2.P.5.3 Validation of analytical procedures
    • 2.P.5.4 Batch analyses
    • 2.P.5.5 Characterization of impurities
    • 2.P.5.6 Justification of specification(s)
  • 2.P.6 Reference standards or materials
  • 2.P.7 Container closure system
  • 2.P.8 Stability
    • 2.P.8.1 Stability summary and conclusion
    • 2.P.8.2 Post-approval stability protocol and stability commitment
    • 2.P.8.3 Stability data
  • 2.P.9 Production documentation
    • 2.P.9.1 Executed production documents
    • 2.P.9.2 Master production documents (MPDs)