Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Critical assessment of the stability section of an Ibuprofen sample dossier: relevance from a scientific point of view ***

Birgit Haas-Heinrich (Abschlußjahr: 2002)

This master thesis deals with the recommendations of stability testing for generic products and analysis a documentation of ibuprofen 200mg film-coated tablets. The relevant stability guidelines reflect the scientific point of view and the current state of the art. These guidelines therefore build the basis for this assessment and are described detailed in the first main part of this master-thesis. The second smaller part deals with the evaluation of the sample documentation.

The main important guideline is "Note for Guidance on Stability Testing: Stability testing of existing active substance and related finished products CPMP/QWP/556/96". At the beginning of 2002 a revision was published, because it was necessary to bring it in line with ICH Q1A (revised) and CTD. The new guideline is still a draft (CPMP/QWP/122/02), but in my opinion significant changes will be introduced. Nevertheless, there are several guidelines which should be taken into consideration. Some of them relate to existing, known drug substances and products. Others deal with new active substances and products, and give useful hints for the stability testing (e.g. Note for Guidance on evaluation of stability data CPMP/ICH/420/02).

The chemical-pharmaceutical documentation for submission should include data of batches with the same composition, dosage form and container (including any secondary packaging and labels) intended for marketing. The manufacturing process of these stability batches should simulate the one used for batches of production size. The test procedures should be the same during all stability tests. The analytical tests used should be fully described and validated. Whenever a change is necessary, the comparability of both methods should be shown by a F- and T-Test. The stability specification should include attributes that are susceptible to change and may have an influence on quality, safety or efficacy, e.g. physical, chemical, biological and microbiological attributes, preservative content and functionality tests. Stability studies should be performed on each strength and, if appropriate, on each container size (e.g. ointments) unless bracketing is used. The number and size of stability batches is influenced by the dosage form and characteristic of the active ingredient. The general case is described in the table below.

Study Storage condition Minimum time period covered by data at submission
Long term 25°C ± 2 °C / 60 % rh ±5 % rh 6 months (if conventional dosage form and stable drug substance) of at minimum two pilot scale batches
12 months (if critical dosage form or unstable drug substance) of at minimum three batches, two of pilot scale, the third one can be smaller
Intermediate 30 °C ± 2°C / 60 % rh ±5% rh 6 months (if significant changes occurred under accelerated testing)
Accelerated 40 °C ± 2°C / 75 % rh ±5% rh 6 months

Drug products packed in semi-permeable containers and products which should be stored in a refrigerator or freezer need other test conditions.

The test intervals at long-term storage - unless bracketing or matrixing is applied - are every three months in the first year, every six months in the second year and then annually until the proposed shelf-life. An accelerated stability study should consist of three time points including the initial and final time point.

Bracketing and matrixing are two possibilities for reduced stability designs. The Note for Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products, ICH Step 4 (CPMP/ICH/4101/00) describes both principles and gives examples for one-half or one-third reduction. These reduced designs can be applied to most types of drug products.

Batches of production scale size and long-term stability data are not always available at the time of submission or approval. In those cases the applicant should make a commitment to fulfil the stability requirements (size and number of stability batches) after approval until the proposed shelf-life.

A statistical evaluation of stability data is recommended according to CPMP/QWP/122/02. Statistical analysis can be useful in the extrapolation and verification of shelf-lives. But not all tested attributes are useful. Quantitative, chemical attributes such as assay, degradation products and preservative content are amenable to linear regression and poolability testing. Where the obtained stability data show little or no variation during long-term and accelerated testing, a statistical analysis is not normally necessary.

On condition that the accelerated stability data show no significant deviation, an extension of shelf-life is justified up to twice the length of the real time studies. An extrapolation is accepted up to a shelf-life of at maximum 36 months.

The acceptance of the documentation depends on the purpose. It is sufficient to document the standard registration in Germany. An annual testing of ibuprofen 200mg film-coated tablets would be appropriate due to the known stability of ibupofen. For a new application in other countries, the data is not sufficient, because the data presented in the documentation of ibuprofen 200mg film-coated tablets do not comply with the "Note for Guidance on Stability Testing of Existing Active Substances and Related Finished Products (CPMP/QWP/556/96)" and its revision CPMP/QWP/122/02. A shelf-life of three years cannot be accepted, because of missing test points, no further testing after six months and missing data of accelerated studies. Indeed, the recommendation is testing every three months in the first year, every six months in the second year and then annually until the end of the proposed shelf-life. But is the availability of data for the third and perhaps 6th or 9th months really relevant for the stability of the product? The available data of 6 or 12 respectively 36 months justify the stability, which have been tested in course of the evaluation of the standard registration and the raw material. In this special case, it depends on the purpose of the documentation as to whether a stability program according CPMP/QWP/122/02 should be carried out. If a decision is made in favour of a full program, bracketing and/or matrixing should be considered. Tests at accelerated conditions are necessary if an extrapolation of data is intended. On the other hand, if the storage condition "Do not store above 25 °C" is labelled, no additional testing is needed. This applies also to the purpose of the documentation as a standard registration. Only if an application for marketing authorisation is intended in other countries, one should choose the stability program according ICH requirements.

The additional data of the second formulation (400 mg ibuprofen film-coated tablets) are also not acceptable. The formulation of both is different, so that a comparability is not given. Despite this, many similarities can be seen, which could justify poolability of both strengths. For example, differences in colourants can be neglected.

The acceptance criteria of the stability specification could be revised concerning disintegration, water content and impurity levels. For disintegration a reduction in accordance to the evaluated values could be made, but is not mandatory. The compliance to Ph. Eur. is relevant. The water content of tablets is interesting enough to be monitored during long-term and accelerated testing. My suggestion is that this test could be included at least for information. The Note of Guidance on Impurity Testing: Impurities in New Drug Products CPMP/ICH/2738/99 has not been considered. Any impurity exceeding the limit of 0.1 % must be identified. A level of max. 0.3 % for single unknown impurities is acceptable, if those impurities were found in the batch of the used drug substance and if they are the same unknown impurities as specified in the Ph.Eur. A value of 0.13 % of unknown impurities requires a change of specification and the identification of the unknown impurities. Problems may appear, if a purchased raw material batch complies to Ph.Eur., but the established value of unknown impurities is higher than 0.1%. Appropriate arrangements must be made in this case (e.g. mandatory specification for the raw material manufacturer).

The whole documentation is characterised by missing (e.g. information about batch sizes, manufacturing date) or superfluous information (repeating of long method descriptions). The size and type of batches are relevant factors for stability evaluation. During scaling-up from pilot to production scale batches, many stability problems may suddenly appear. On the other hand, a description of the methods without validation data is useful in this chapter, if the drawing-up is made by the stability laboratory. Mistakes in cross-referencing could be avoided. A review (countercheck) by an independent person is always useful to correct mistakes, typing or copy errors.

Stability testing according to the relevant guidelines is mandatory for submission. A sufficient data basis and a good evaluation are of advantage for the applicant and for the authority. The knowledge about the stability of a formulation is of great importance concerning quality, safety and efficacy. In addition, a follow-up stability test carried out at one batch per year, should be introduced on a company's own initiative. These tests are mandatory in the U.S., but not in the EU.

My experience is that it is difficult to persuade authorities about sufficient stability testing when it is not exactly in line with the guidelines. Within the EU, one could discuss openly with competent experts of the authorities about different points of view. In countries outside the EU, the authorities often do not accept any variation of CPMP- or ICH-guidelines. This may be related to inflexibility, or to the level of training and knowledge, or to the fact that the applicant is a generic company.

Pages: 127 (including annexes)