Open Access

Corina Becker

• A generic drug product (World Health Organization (WHO) terminology: multisource product) is usually marketed and manufactured after the expiry date of the innovator’s patent. Generic drugs are less expensive than the innovator products because generic manufacturers do not have to amortize the investment costs of research, development, marketing, and promotion. Multisource products must contain the same active pharmaceutical ingredients (APIs) as the original formulation and have to be shown to be interchangeable with the original formulation. Multisource products have to be shown bioequivalent to the innovator counterpart with respect to pharmacokinetic and pharmacodynamic properties. Multisource products are therefore identical in dose, strength, route of administration, safety, efficacy, and intended use. Bioequivalence can be demonstrated by in vitro dissolution, pharmacokinetic, pharmacodynamic or clinical studies. Since 2000, the U.S. Food and Drug Administration (FDA) allows the approval of certain multisource products solely on the basis of in vitro studies, i.e. by waiving in vivo studies in humans (“Biowaiver”), based on the Biopharmaceutics Classification Scheme (BCS). The BCS characterizes APIs by their solubility and permeability in the gastrointestinal tract (GIT). The different BCS Classes I-IV (Class I: high solubility, high permeability; Class II: low solubility, high permeability; Class III: high solubility, low permeability and Class IV: low solubility, low permeability) result from all possible combinations of high and low solubility with high and low permeability. Since the adoption of the BCS by the FDA in 1995, the BCS criteria have been under continuous development. In 2006, the WHO has released the most recent bioequivalence guidance including relaxed criteria for bioequivalence studies based on modified BCS criteria. According to this guidance, APIs belonging to the BCS classes I – and under defined conditions - II and III – are eligible for a biowaiver-based approval. The principal objective of this work was to characterize the first-line anti tuberculosis APIs, isoniazid, pyrazinamide, ethambutol dihydrochloride and rifampicin, according to their physicochemical, biopharmaceutical, pharmacokinetic and pharmacological properties and to classify them according to the BCS. Ethambutol dihydrochloride and isoniazid were classified as borderline BCS class I/III APIs. Pyrazinamide was classified as a BCS class III and rifampicin as a BCS class II API. Based on the BCS classification and the additional criteria defined in the WHO bioequivalence guidance, the possibility of biowaiver-based approval for immediate release (immediate release) solid oral dosage forms containing the first-line antituberculosis drugs was evaluated. A biowaiver-based approval with defined constraints was recommended for immediate release solid oral dosage forms containing isoniazid (interaction with reducing sugars), pyrazinamide and ethambutol dihydrochloride (relative narrow therapeutic index). Rifampicin was classified as a BCS class II API, and it was concluded that rifampicin containing solid oral immediate release drug products as well as Scale-Up and Post-Approval Changes (SUPAC) changes should not be approved by a biowaiver on the following basis: (i) its solubility and dissolution are highly variable due to polymorphism and instability, (ii) concomitant intake of food and antacids reduces its absorption and bioavailability, (iii) no in vitro predictive dissolution test has been found which correlates to in vivo absorption and (iv) several publications reporting cases of non-bioequivalent and bioinequivalent rifampicin products have been located in the literature. Thus, it is recommended that bioequivalence of rifampicin containing solid oral immediate release drug products should be established by in vivo pharmacokinetic studies in humans. This risk-benefit benefit assessment of a biowaiver-based approval was presented as a poster at the American Association of Pharmaceutical Scientists (AAPS) 2005 and subsequently published as “Biowaiver Monographs” in the Journal of Pharmaceutical Sciences. Based on the assessment of the dissolution properties of the antituberculosis drugs for a biowaiver approval, quality control dissolution methodologies for the International Pharmacopoeia (Pharm. Int.) were developed, presented at the WHO expert meeting and adopted in the Pharm. Int. (http://www.who.int/medicines/publications/pharmprep/OMS_TRS_948.pdf). Additionally, preliminary biowaiver recommendations were also developed for four firstline antimalarial drugs listed on the WHO Essential Medicines List (EML): Quinine, as both the hydrochloride and sulphate, and proguanil hydrochloride were classified as borderline BCS class I/III APIs. Since quinine is a narrow therapeutic index drug and many cases of non-bioequivalence have been reported in the literature, a biowaiverbased approval was not recommended. For solid oral immediate release dosage forms containing proguanil a biowaiver-based approval was recommended under the condition that they dissolve very rapidly. Primaquine phosphate was classified as a BCS class I API. Therefore, a biowaiver-based approval was recommended for immediate release solid oral dosage forms containing primaquine phosphate. Mefloquine hydrochloride was classified as a basic, BCS class IV/II API, making it ineligible for the biowaiver. Additionally, reports of non-bioequivalence and a narrow therapeutic index were found in the scientific literature. Consequently, bioequivalence of solid oral immediate release dosage forms containing mefloquine hydrochloride should be established by in vivo pharmacokinetic studies. The results for quinine hydrochloride and sulphate, proguanil hydrochloride, primaquine diphosphate and mefloquine hydrochloride were presented as a poster at the Pharmaceutical Sciences World Congress (PSWC) 2007 and published as a WHO Collaborating Center Report in June 2006. The aim of this project was to collect, evaluate, generate and publish relevant information for a biowaiver-based approval of essential medicines in order to provide a summary to local regulatory authorities. This information complements the selected list of essential medicines by providing information about the biopharmaceutical properties and pharmaceutical quality of solid oral immediate release dosage forms containing these APIs. The aim of the biowaiver project, inspired by the WHO and brought in life by the International Pharmaceutical Federation (FIP), is to enable access to essential medicines in standardized quality at an affordable price. In this work, a significant contribution to this aim in the form of four biowaiver monographs for the antituberculosis drugs and several reports on the antimalarials has been achieved.
• Nach Ablauf des Patentes der Erstzulassung eines Arzneistoffes (Originalpräparat) mit etablierter Wirksamkeit, Sicherheit und Qualität ist es erlaubt, Nachahmerpräparate (Generika) mit diesem Arzneistoff zuzulassen. Als Generikum bezeichnet man ein Arzneimittel, welches den gleichen Wirkstoff eines bereits auf dem Markt befindlichen Medikaments enthält. Von dem Originalpräparat kann sich das Generikum bezüglich der enthaltenen Hilfsstoffen und der Herstellungstechnologie unterscheiden, muss aber dem Originalpräparat in dessen beanspruchter/n Indikation(en) äquivalent sein. Üblicherweise werden Generika mittels einer bezugnehmenden Arzneimittelzulassung zugelassen. Dabei muss Bioäquivalenz zum Orginalpräparat gezeigt werden. Zwei Produkte bezeichnet man als bioäquivalent, wenn eine äquivalente Bioverfügbarkeit beider Präparate, welche den identischen Wirkstoff enthalten, mittels geeigneter Testmethoden nachgewiesen wurde. Derartige Testmethoden wurden in den Bioäquivalenzrichtlinien unter anderem der US-amerikanischen Behörde für Lebensmittel- und Arzneimittelsicherheit (FDA)7, der Europäischen Arzneimittelagentur (EMEA)8 und der Weltgesundheitsorganisation (WHO)19 festgelegt. Diese Testmethoden können vergleichende pharmakokinetische, pharmakodynamische oder klinische Studien im Menschen sein. Dabei muss laut der Bioäquivalenzrichtlinie z.B. der WHO der 90-%-Vertrauensbereich des Quotienten der für die zu vergleichenden Kenngrößen, meistens Cmax und AUC, ermittelten durchschnittlichen Werte für Testprodukt und Originalprodukt innerhalb fest definierter Grenzen liegen (üblicherweise 80–125 %). Die Auswahl der Kenngrößen und das Studiendesign hängen unter anderem von der Indikation und der Darreichungsform des Arzneimittels ab. Alternativ können, unter bestimmten Bedingungen, diese Bioäquivalenzstudien im Menschen durch in vitro Freisetzungsstudien ersetzt und somit das Zulassungsverfahren vereinfacht und beschleunigt werden. Dieses vereinfachte Zulassungsverfahren, bei dem Studien im Menschen ausgesetzt „waived“ werden, wird als Biowaiver-Zulassung bezeichnet. ...