4.2.1.P.1 Description and composition
In the case of any modification of the authorised product other than repackaging, the complete quantitative composition of the preparation should be specified. All additional substances/materials added to the authorised product should be listed with reference to pharmacopoeial or in-house monographs. For the authorised product itself, reference to the name and marketing authorisation (MA) number will suffice, including a copy of the SPC/PIL in Module 1.
4.2.1.P.2 Pharmaceutical development
The modifications carried out on the authorised product should be described and their influence on the quality of the product discussed. Special focus should be assigned to all parameters relevant for the function, stability and efficacy of the new drug, such as in vitro-dissolution and pH-value. It should be demonstrated that these parameters remain comparable to those of the unmodified product.
Compatibility with other solvents (that are not stated in the original SmPC) used for drug product reconstitution and dilution should be demonstrated. Compatibility studies reflecting the practice described in the clinical protocol (e.g. dispersion of a tablet or content of the hard capsule in water/juice/food) should be performed in case of unstable products and/or in case of preparation in advance.
In case of solid oral dosage forms, comparative dissolution profiles of both original and modified product should be provided to ensure unchanged bio-pharmaceutical properties. In those cases where comparability cannot be established in vitro, additional clinical data to support equivalence may be necessary.
4.2.1.P.3 Manufacture
4.2.1.P.3.1 Manufacturer(s) related to the modification
The name(s) and address(es) and responsibilities of all manufacturer(s), including contractors, and each proposed site involved in the modification, packaging/assembly and testing of the modified product should be provided. In case that multiple manufacturers contribute to the manufacture of the IP, their respective responsibilities need to be clearly stated. Sites responsible for import or/and QP release in the Kingdom of Saudi Arabia (KSA) should be also stated.
When re-packaging and or re-labelling is carried out at a hospital, health centre or clinic where the investigational product is to be used for the trial exclusively at those institutions, and where an exemption from the need to hold a manufacturing authorisation, it is not necessary to provide the names and addresses of those institutions in this section. If relevant, it is sufficient to indicate that these activities will take place.
4.2.1.P.3.2 Batch formula
The batch formula for the batch intended to be used during the clinical trial should be presented. This does not apply to authorised products which are only re-packaged.
4.2.1.P.3.3 Description of manufacturing process and process controls
All steps of the modification of the authorised new drug should be described, including in- process controls that are carried out. For details, reference is made to section. 2.2.1.P.3.3).
4.2.1.P.4 Control of excipients
4.2.1.P.4.1 Specifications
References to the United States Pharmacopoeia, European Pharmacopoeia, International Pharmacopoeia or the British Pharmacopoeia should be indicated. For excipients not described in one of the mentioned pharmacopoeias, reference to the relevant food- chemical regulations (e.g. FCC) can be made. For excipient mixtures composed of pharmacopoeial substances, e.g. pre-fabricated dry mix for film-coating, a general specification of the mixture will suffice. For excipients not covered by any of the afore-mentioned standards, an in-house monograph should be provided. Specification for capsule shells should be provided.
4.2.P.4.2 Analytical procedures
In cases where reference to a pharmacopoeial monograph listed under 4.2.1.P.4.1 cannot be made, the analytical methods used should be indicated.
4.2.1.P.4.3 Validation of analytical procedures
Not applicable.
4.2.1.P.4.4 Justification of specifications
Not applicable.
4.2.1.P.4.5 Excipients of animal or human origin
Cf. Appendix 7.2.1. A.2.
4.2.1.P.5 Control of the modified authorised product
4.2.1.P.5.1 Specifications
The chosen release and shelf-life specifications of the modified authorised product should be submitted, including test methods and acceptance criteria. Generally, they should include description and identification of the drug substance as well as the control of important pharmaceutical and technological properties, such as dissolution. Where an intact solid oral dosage form that is easily identifiable by its color, shape and marking is encapsulated, identification of the active substance may not be necessary, and visual examination may suffice for identification. Depending on the degree of modification of the authorised product, additional quality criteria, e.g. determination of the drug substance(s) and impurities/degradants, may need to be specified and tested.
4.2.1.P.5.2 Analytical procedures
For parameters relevant to the performance of the modified authorised product, e.g. dissolution, the methods should be described. It is not necessary to provide a detailed description of the analytical procedures (see definition of analytical methods vs. analytical procedures in chapter 1.5 General considerations).
4.2.1.P.5.3 Validation of analytical procedures
The suitability of the analytical methods used should be demonstrated. A tabulated summary of the results of validation of the analytical methods should be provided (e.g. results or values found for specificity, linearity, range, accuracy, precision, quantification and detection limit, as appropriate). It is not necessary to provide a full validation report.
4.2.1.P.5.4 Batch analyses
Results or certificates of analysis for the batch of modified authorised product to be used in the clinical trial or of a representative batch should be provided.
In case of more than one bulk manufacturing sites, it is necessary to provide results for batches which have been produced by each of the bulk manufacturing sites relevant for the current trial unless otherwise justified, (e.g. where one legal entity has multiple sites (in the same country), then batch analysis data from one site only would be sufficient).
The batch number, batch size, manufacturing site, manufacturing date, control methods, acceptance criteria and the test results should be listed.
4.2.1.P.5.5 Characterisation of impurities
In those cases, where the authorised product has undergone significant modification by the sponsor,
e.g. has been processed with an excipient hitherto not present in the formulation with a likely impact on product stability, and the original product is not known to be stable under normal conditions, special emphasis should be given to demonstrating that the impurity profile has not changed compared to the original product. For stable authorised products, where a small degree of modification has been undertaken by the sponsor, e.g. where an intact tablet is encapsulated using the ingredients already present in the tablet, justification for not quantifying impurities will suffice This is not required for authorised products which are only re- packaged.
4.2.1.P.5.6 Justification of specification(s)
A justification of specification(s) will only be required in cases where a significant modification of the authorised product may affect the product’s performance or safety.
4.2.1.P.7 Container closure system
The type of immediate packaging, material and package size(s) should be specified. If materials other than those authorised are used, a description and specifications should be provided. Where appropriate, reference should be made to the relevant pharmacopoeial monograph. If the test/comparator product is packed in a non-standard administration device, or if non-compendial materials are used, a description and specifications should be provided.
4.2.1.P.8 Stability
The applicant or sponsor of the clinical trial has to ensure that the modified test/comparator product is stable for at least the anticipated duration of the clinical trial in which it will be used.
In the case of any modification with a likely significant impact on product stability, a minimum of stability data on the modified authorised product should be available, depending on the length of the planned clinical trial, prior to the start of the clinical trial in order to allow an assessment of the impact of the modifications on product safety and stability. The available stability data should be presented in a tabulated form. An evaluation of the available data and justification of the proposed shelf-life to be assigned to the IP in the clinical trial should be provided. Any degree of extrapolation may not exceed the shelf-life originally assigned to the specific batch of authorised product by its MAH.
Shelf life extension without a substantial modification submission can be approved under the same conditions as described in the section 2.2.1.P.8.
In the case of only minor modifications, a justification of the stability over the intended trial period may be acceptable.
In-use stability studies should be performed in case of use of the comparator product in different conditions as those described in the SPC (according to the clinical protocol), if not otherwise justified (the same requirements as defined in section 2.2.1.P.8 apply).