3.2 Finished Pharmaceutical Product:
“3.2.P.2.2”
3.2.1 Formulation Development:
3.2.P.2.2.1 A brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo
studies (e.g. bioequivalence) should be discussed when appropriate.
When preparing the PD for submission, the data requirements of the NMRA regarding formulation development may depend on whether the multi source product has been newly developed by the applicant or manufacturer or whether it is an established multi source product.
The WHO Prequalification of Medicines Programme defines an established multi source product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multi source product, all sections of P.2.2.1 of the dossier should usually be completed with the exception of P.2.2.1 (a). In addition, a product quality review should usually be provided in the PD as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multi source (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).
The requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO guidelines on registration requirements to establish interchangeability for multi source (generic) pharmaceutical products (7) can be consulted.
Tablet scoring may be recommended or required in certain jurisdictions or, for example, when scoring is indicated in the WHO invitation for expression of interest, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.
If the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should usually include a description of the test method, individual values, mean and relative standard deviation of the results. Uniformity testing (i.e. content uniformity or mass variation, depending on the requirement for the whole tablet) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an example the number of units (i.e. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 10 quarters for quadrisected tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions only needs to be demonstrated once and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labeling or package leaflet) should reflect the presence of a score line.
If a paediatric dose is to be obtained by splitting a tablet, a demonstration of content uniformity of tablet fragments may be required.
For modified-release tablets designed to be divided into equal halves, demonstration of dissolution profile similarity of the tablet halves against the whole tablet may be required.
Where relevant, labeling should state that the score line is only intended to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In this case a demonstration of uniformity is unlikely to be required.
In vitro dissolution or drug release
A discussion should usually be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile.
The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) are usually required in the PD. Data should also usually demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.
Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1 of the WHO Guidelines on submission of documentation for a multi source (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).
In the case of rapidly dissolving FPPs containing highly soluble APIs (BCS classes 1 and 3), a single-point dissolution test limit of 80% in 30 minutes or less is considered sufficient as a routine QC test for batch-to-batch uniformity. For slowly dissolving or poorly water-soluble APIs (BCS classes 2 and 4) in immediate-release products, a two-point dissolution range (a dissolution window), one at an early time-point (e.g. Q = 60% in 45 minutes) and the other at a later point (e.g. Q = 80% in 90 minutes), is recommended to characterize the quality of the product. Note that in some cases the later point may be lower than 80% if a plateau is reached.
Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine QC. Preferably, this test should possess in vitro–in vivo correlation. Results demonstrating the effect of pH on the dissolution profile are usually required, if appropriate for the type of dosage form.
For extended-release FPPs the testing conditions should be set to cover the entire period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test period, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or ± 12.5% of the targeted value. Dissolution results are usually required for several lots including those used for pharmacokinetic and bioavailability or biowaiver studies.
The dissolution acceptance limit(s) should also be incorporated into the stability programmes.
Where there are scientific grounds that the defined release characteristics of oral pharmaceutical products may be adversely affected by the presence of alcohol, e.g. for modified-release products containing opiates, 5%, 10% and 20% ethanol should be added to the dissolution medium proposed for routine testing in order to demonstrate that no dose dumping will occur through intake with alcoholic beverages.
3.2.2 Overages:
3.2.P.2.2.2 Any overages in the formulation(s) described in 3.2.P.1 should be justified. Justification of an overage to compensate for loss during manufacture should usually be provided in the PD, including the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).
Overages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.
3.2.3 Physicochemical and Biological Properties:
3.2.P.2.2.3 Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency and/or immunological activity, should be addressed.
Pharmaceutical Development of Multi source (generic) Finished Pharmaceutical Products – points to consider, (Annex 3, WHO Technical Report Series 970, 2012)
