SCIENTIFIC DISCUSSION

Transcription

1 SCIENTIFIC DISCUSSION Name of the Finished Pharmaceutical Product: Manufacturer of Prequalified Product: Active Pharmaceutical Ingredients (APIs): Pharmaco-therapeutic group (ATC Code): Therapeutic indication: Lopinavir/Ritonavir tablets 200 mg/50 mg * Matrix Laboratories Limited F-4, F-12, Malegaon M.I.D.C Sinnar Nashik Maharashtra India Lopinavir + Ritonavir Antivirals for systemic use, protease inhibitors (J05AE06 and J05AE03) Lopinavir/Ritonavir tablets 200 mg/50 mg is indicated for the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infected adults and children. * Trade names are not prequalified by WHO. This is under local DRA responsibility. Throughout this WHOPAR the proprietary name is given as an example only. Page 1 of 5

2 1. Introduction Lopinavir/Ritonavir tablets 200 mg/50 mg tablets is indicated for the treatment of infected adults and children weighing 25 kg or more who are infected with human immunodeficiency virus type 1 (HIV- 1). 2. Assessment of Quality The assessment was done according to SOP 20 of the WHO Prequalification programme. Active Pharmaceutical Ingredients (APIs) Lopinavir and ritonavir Lopinavir and ritonavir are class 4/2 APIs according to Biopharmaceutics Classification System (WHO Technical Report Series 937, Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms). Ritonavir Ritonavir is described in the Ph.Int, Ph.Eur. and USP. The API is obtained from within the Matrix group of companies and the APIMF has been accepted through WHO s APIMF procedure. Ritonavir has four chiral centres, is practically insoluble in water and is known to exhibit polymorphism. The manufacture of ritonavir entails several steps and is stereoselective producing the desired stereoisomer. The manufacturing process has been validated in all respects and found to be consistent. Polymorphic Form II is consistently produced through control of the final recrystallisation step, which includes seeding. The API is adequately controlled by its set of quality specifications which is pharmacopoeial based, with additional in-house specifications including residual solvents. Based on the results of stability testing conducted according to the requirements of WHO, a retest period of 36 months was approved for ritonavir when stored not above 30ºC. Lopinavir By the time of submission lopinavir was not described in any of the recognized pharmacopoeia. The API is obtained from within the Matrix group of companies and the APIMF has been accepted through WHO s APIMF procedure. Lopinavir has four chiral centres and exhibits potential isomerism. It is soluble in organic solvents like methanol, ethanol, dichloromethane and DMF, but practically insoluble in water and in aqueous buffers from ph 1 to ph 8. Lopinavir is hygroscopic and is known to exhibit polymorphism and exists in various polymorphic forms. Matrix produces the type-i higher hydrate form. The manufacture of ritonavir entails several steps and is stereoselective producing the desired stereoisomer. The manufacturing process has been validated and found to be consistent. The API is adequately controlled by its set of quality specifications. The specifications are in line with ICH guidelines Q6A and Q3A(R) and have been justified. The analytical methods adequately validated. Based on the results of stability testing conducted according to the requirements of WHO, a retest period of 36 months was approved for lopinavir when stored not above 30ºC under nitrogen. Other ingredients Other ingredients used in the core tablet formulation include colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate, all being compendial controlled. The film coating contains colloidal anhydrous silica, hydroxypropyl cellulose, hypromellose, iron oxide yellow, polyethylene glycol 3350, polyethylene glycol 400, polysorbate 80, talc and titanium dioxide. Finished Pharmaceutical Product (FPP) Pharmaceutical development Lopinavir/Ritonavir tablets 200 mg/50 mg are light yellow to yellow coloured, film-coated, ovaloid tablets, debossed with "M124" on one side and plain on other side. Page 2 of 5

3 The primary packs are cold-formed aluminium blisters sealed with an aluminium foil lid (12 tablets per blister card, 10 cards per carton) and round, white, opaque, induction-sealed HDPE bottles fitted with white, opaque tamper-evident polypropylene closures containing desiccant (120 tablets per bottle). The development of the final composition of Lopinavir/Ritonavir tablets 200 mg/50 mg has been described. The objective was to develop a stable product, bioequivalent to the innovator product, Kaletra 200mg/50mg Tablets. The tablets have been developed as solid dosage form for oral administration. Lopinavir and ritonavir are practically insoluble in water, to such an extent that when administered as tablet prepared by conventional techniques, the oral bioavailability of these APIs is negligible. In order to have clinically significant concentrations of these drugs, the reference product (Kaletra tablets) has been formulated using the melt extrusion technique in which both APIs are present in the solid dispersion form. In order to make a generic bioequivalent product, it was decided to explore the melt granulation and solvent evaporation techniques for making solid dispersions. Several attempts at the melt granulation process gave unsatisfactory results. The solvent evaporation approach resulted in dissolution properties comparable to that of the innovator product. The critical process, drying, was optimized in terms of stability and release characteristics. The studies resulted in the manufacture of a lopinavir/ritonavir premix. The premix and excipients are sifted, blended together and compressed. The tablets are finally coated. Comparative in-vitro dissolution studies showed that Lopinavir/Ritonavir tablets 200 mg/50 mg have similar dissolution characteristics to Kaletra 200mg/50mg tablets in the media studied. It has furthermore been demonstrated that the multipoint dissolution characteristics of the generic product are retained during the shelf life. Appropriate in-process controls were set to ensure batch-to-batch reproducibility. Validation data presented for three production scale batches, on the lower production range end, demonstrated the consistency of the process and the quality of the product. The applicant committed to conduct process validation studies on production scale batches at the high end of the proposed production range, according to agreed protocols. The proposed specifications are regarded adequate for ensuring consistent quality for this finished pharmaceutical product. A 2-point dissolution requirement has been set, namely at 45 and at 90 minutes. The specifications are supported by batch analytical and stability data. Stability testing Stability studies have been performed at 30 C/75%RH (zone IVb) as long-term conditions and for six months at accelerated conditions. At the time of the prequalification, a shelf-life of 24 months has been allowed for the FPP when stored not above 30 C. Conclusions The quality part of the dossier is accepted. 3. Assessment of Bioequivalence The following bioequivalence study has been performed in 2007 according to internationally accepted guidelines. A randomized, open label, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Lopinavir/Ritonavir tablets 200 mg/50 mg of Matrix Laboratories Limited, Hyderabad, India and Kaletra (Lopinavir 200 mg + Ritonavir 50 mg) tablets of Abbott Laboratories, USA, in healthy human adult subjects, under fasting conditions (study no. 905/06). The objective of the study was to compare the bioavailability of the stated Lopinavir/ritonavir 200mg/50 mg fixed dose combination tablet manufactured by Matrix Laboratories Ltd., India (test drug) with the same dose of the reference formulation (Kaletra, Abbott Laboratories) and to assess bioequivalence. The comparison was performed as a single centre, open label, randomized, crossover Page 3 of 5

4 study in healthy male subjects under fasting conditions. Each subject was assigned to receive each of the following two treatments in a randomized fashion: Treatment T: Treatment R: Test Lopinavir/ritonavir tablets 200 mg/50 mg (lopinavir/ritonavir 200mg/50 mg) Batch no. LORA Reference Kaletra tablet (lopinavir/ritonavir 200mg/50 mg) Batch no Y40. A 7-day wash-out period was observed between administration of test and references. Serial blood samples (1 pre-dose sample and 20 samples within 24 h post dose) were taken during each study period to obtain bioavailability characteristics AUC, C max and t max for bioequivalence evaluation. Drug concentrations for lopinavir and ritonavir were analyzed using a validated LC-MS method. The limit of quantification was stated to be about 100 ng/ml for lopinavir and about 10 ng/ml for ritonavir. The study was performed with 32 participants; data generated from a total of 31 subjects were utilized for analysis to establish pharmacokinetic parameters and assess bioequivalence. Arithmetic mean and geometric mean values of the pharmacokinetic variables for lopinavir and ritonavir as well as statistical results are summarised in the following tables: Pharmacokinetic Parameter Test formulation (T) Lopinavir Reference (R) log-transformed parameters Ratio Conventional T/R (%) 90% CI (ANOVAlog) t max (h) 3.50 ± ± C max (µg/ml) 3.89 ± ± (3.53) (3.43) AUC 0-t (µg.h/ml) 33.9 ± ± (28.6) (30.1) AUC 0-inf (µg.h/ml) 36.4 ± ± (30.7) (32.1) * geometric mean Pharmacokinetic Parameter Test formulation (T) Ritonavir Reference (R) log-transformed parameters Ratio Conventional T/R (%) 90% CI (ANOVAlog) t max (h) 3.66 ± ± C max (ng/ml) 178 ± ± (154) (152) AUC 0-t (ng.h/ml) 1429 ± ± (1184) (1251) AUC 0-inf (ng.h/ml) 1560 ± ± (1316) (1393) * geometric mean The results of the study show that preset acceptance limits of % are met by both AUC and C max values regarding lopinavir and ritonavir. Accordingly, the test fixed dose combination tablet Lopinavir/ritonavir tablets 200 mg/50 mg meets the criteria for bioequivalence with regard to rate and extent of absorption and is therefore bioequivalent to the reference Kaletra (Abbott Laboratories). Page 4 of 5

5 4. Summary of Product Safety and Efficacy Lopinavir/Ritonavir tablets 200 mg/50 mg have been shown to conform to the same appropriate standards of quality, efficacy and safety as those required of the reference product. According to the submitted data on quality and bioavailability it is pharmaceutically and therapeutically equivalent and thus interchangeable with the reference product Kaletra, for which benefits have been proven in terms of virological and immunological efficacy. The clinical safety of this product is considered to be acceptable when guidance and restrictions presented in the Summary of Product Characteristics are taken into consideration. Reference is made to the SPC (WHOPAR part 4) for data on clinical safety. 5. Benefit risk assessment and overall conclusion Quality The quality of this product is considered to be acceptable when used in accordance with the conditions defined in the SPC. Physicochemical and biological aspects relevant to the uniform clinical performance of the product have been investigated and are controlled in a satisfactory way. Bioequivalence Lopinavir/Ritonavir tablets 200 mg/50 mg has shown to be bioequivalent to the reference formulation Kaletra (Abbott Laboratories, USA). Efficacy and Safety Regarding clinical efficacy and safety, Lopinavir/Ritonavir tablets 200 mg/50 mg is considered effective and safe to use when the guidance and restrictions presented in the Summary of Product Characteristics are taken into consideration. Benefit Risk Assessment Based on the WHO assessment of data on quality and bioequivalence the team of assessors considered by consensus that the benefit risk profile of Lopinavir/Ritonavir tablets 200 mg/50 mg was acceptable for the following indication: for the treatment of HIV-1 infected adults and children (weighing 25 kg or more) in combination with other antiretroviral agents and has advised to include Lopinavir/Ritonavir tablets 200 mg/50 mg, manufactured at Matrix Laboratories Limited, F-4, F-12, Malegaon M.I.D.C, Sinna, Nashik , Maharashtra, India, in the list of prequalified medicinal products. Page 5 of 5