Experience of Application of the Dissolution Test and Biowaiver Procedure to Evaluation of the Generic Drugs Represented in Russian Pharmaceutical Market

Smehova I.Ye., assistant professor, Ph.D., Ladutko Yu.M., assistant professor, Ph.D.

Saint Petersburg State Chemical Pharmaceutical Academy, Russia

Resume: The application of the Dissolution test and Biowaiver procedure for the evaluation of pharmaceutical and bioequivalence in vitro for original (brand name) and generic drugs marketed in Russia is represented in the article. The received data allows making the conclusion about the possibility of carrying out biowaiver procedure for the establishment of bioequivalence for nearly 30% of generics in each of studied INN.

Key words: dissolution, in vitro, biowaiver, generic drug

The aim of this article is to share the experience of application of the dissolution test and biowaiver procedure to evaluation of the generic drugs marketed in Russia and to state the results of work in this field carried out in Saint Petersburg State Chemical Pharmaceutical Academy (SPCPA) in the Department of the Technology of Medicinal forms.

Today generics are widely used in different countries. In Russia their sales volume is about 80%.

In order to ensure interchangeability in pharmacotherapy, the multisource product must be pharmaceutically, therapeutically equivalent and bioequivalent to the comparator product.

Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards.

Dissolution test is one of the tests to prove the pharmaceutical equivalence of the generics, it also allows prediction of their efficacy in vivo under some conditions.

The test technique is issued in the form of state standard as a part of the normative documentation obligatory for performance at acknowledgement of quality of medicinal products with the same active component.

Generic medicines should correspond to the same quality requirements as the brand name medication.

But in Russia in last two decades because of the lack of the uniform state standards many manufacturers worked out their own Dissolution tests for the generics they produced. This was often connected with inaccessibility of the comparator product test techniques or with inability of generics to meet the requirements of the original drugs. Lack of correspondence is determined by the absence of taking the pharmaceutical factors into consideration. Substances of other quality or possessing the other physicochemical properties (such as dispersion, solubility, polymorph modifications) are often used in generics manufacturing. The differences may be also caused by qualitative and quantitative composition of pharmaceutical excipients, by technology, by used equipment, et cetera.

Because of the aforesaid verification of generic medicines in all kinds of equivalence and working out appropriate documentation is of current importance. It is particularly important for the generics used for treatment of the socially significant diseases.

Investigation in SPCPA are carried out in the fields of the evaluation of pharmaceutical equivalence (including the Dissolution testing) and the establishment of opportunity of the determination of bioequivalence using the biowaiver procedure.

22 international nonproprietary name (INN) immediate release generic tablets, coated tablets, capsules of domestic and foreign production were chosen as the objects for the pharmaceutical equivalence estimation (amlodipine, ampicilline, atenolol, acyclovir, verapamil, diclofenac sodium, drotaverine, ibuprofen, indapamide, indometacin, acetylsalicylic acid, co-trimoxazol, metamizol sodium, metoclopramide, metronidazol, nifedipine, papaverin, paracetamol, ranitidine, rifampicin, trimetazidine, furosemide). These medications are referred to different clinical-pharmacological groups. The biggest part of the objects is included in the WHO list of essential medicines [1].

It was established that only 25% of methods and requirements of generic’s Dissolution tests correspond to the same of the original medicines.

Some manufacturers try to obtain the correspondence of their generics to the requirements of the comparator product’s dissolution test changing the conditions of carrying it out. For that some surface-active materials or organic solutions are unreasonably added to the medium, or pH is changed, or the medium is gained in volume, sometimes the rotation speed of the apparatus or the dissolution time are increased or the dissolution rate is reduced, etc. Satisfactory results obtained under such conditions can not guarantee the equivalence of the generic to the original medicine.

We studied the dissolution of more than 150 domestic and foreign generics by different methods including the methods of the original medicines or inscribed in the USP [2]. And for all that we compared the dissolution profiles calculating the difference and the similarity factors. It was established that generics meet the requirements of their normative document. And some of them do not fit with the requirements of the comparator medicine.

The conditions of the comparator’s dissolution tests usually allow distinguishing of generics. That’s why this methods are appropriate to be used both in quality control of the produced medicines and in assessment of pharmaceutical equivalence.

As an example the results of the analysis of dissolution tests and experimentally obtained data for verapamil generic tablets 40 mg and 80 mg (“Isoptin” was used as the comparator product) are represented. On the basis of the similarity factor the conclusion about pharmaceutical equivalence of 2 out of 6 examined generics was made.

In our opinion to prevent the manufacturing of pharmaceutically nonequivalent drugs and to improve the quality of solid oral dosage forms use of the single Dissolution test is necessary for the medicines with the same active ingredient.

Pharmaceutical equivalence appreciates mainly merchandising characteristics and does not guarantee therapeutic equivalence. One of the methods to confirm it is the proof of biological equivalence of the medicines. That is why the other line of our investigations is the evaluation of bioequivalence.

In most cases for bioequivalence evaluation pharmacokinetics investigations and in vitro trials are carried out. The first of them are rather expensive and enduring. That’s why the evaluation of bioequivalence by in vitro biowaiver procedure [3] is of current importance in pharmaceutical practice all over the world including Russia.

For evaluation the availability of this procedure we carried out grouping into divisions of biopharmaceutical classification the immediate release solid oral dosage forms included into the Russian Essential Medicines List and into the Health Ministry's Additional Medications Provision/Supply program List (picture 1).

Picture 1. Distribution of immediate release solid oral dosage forms included into the Essential Medicines List into the classes of Biopharmaceutical Classification System (EML - Essential Medicines List; AML - the Health Ministry's Additional Medications Provision/Supply program List; EML WHO - WHO Essential Medicines List)

It was established that there is of about 50% of single-component immediate release solid oral dosage forms in the Essential Medicines List whereas there are about 80% of them in the Health Ministry's Additional Medications Provision/Supply program List. The class is known for almost 51% of drugs included into the Essential Medicines List and 38,2% of drugs included into the Health Ministry's Additional Medications Provision/Supply program List. We rated to the “mixed” group the medicines the class for which is not specified yet. For comparison the data obtained by other authors for the WHO Essential Medicines List are represented in the picture [4, 5].

Multicomponent medicines for the active ingredients of which the class has been determined are prospective for the evaluation of bioequivalence using the biowaiver procedure.

So we suppose that the bioequivalence for more than 50% of medicines of the 1 and 3 BCS classes included into the aforenamed Lists may be evaluated by biowaiver procedure. According to the selection scheme the objects for the evaluation of bioequivalence by biowaiver procedure were chosen. There were the generic medicines of 9 INN of different BCS classes presented in the Russian pharmaceutical market (atenolol, acyclovir, indapamide, diclofenac, drotaverine, metoclopramide, metronidazole, ranitidine, trimetazidine). Some multicomponent medicines containing ascorbic acid and rutoside, papaverine and bendazol, drotaverine and paracetamol of domestic and foreign manufacturers were also chosen. The choice is also caused by the large amount of the generics of the selected medicines in Russia.

Analysis of more than 50 medicines of the aforesaid INN appeared that pharmaceutical substances and excipients in biopharmaceutical and in physicochemical properties correspond to the essential requirements for bioequivalence in vitro trials.

At the same time not for all of the investigated generics the dissolution profiles fit with requirements: while carrying out the in vitro test they dissolved with the other rate than the comparator product. There was no similarity of the dissolution profiles in different media. That is why for these generics it is compulsory to confirm bioequivalence to the comparator product in vivo.

As an example we give dissolution profiles of acyclovir from tablets (comparator product is Zovirax) (picture 2). Equivalence of generic medicine to the comparator was established without mathematical treatment because in all media there dissolved more than 85% of acyclovir in 15 minutes both from Zovirax and its generic.

Picture 2. Dissolution profiles of acyclovir in different media

There are also given the dissolution profiles of paracetamol and drotaverine from multicomponent medicines with the same composition in three media (picture 3). Medical products are not equivalent because they have no similarity in dissolution profiles of drotaverine in one dissolution media.

Picture 3. Dissolution profiles of paracetamol and drotaverine from multicomponent medicines

The received data allows making the conclusion about the possibility of carrying out biowaiver procedure for the establishment of bioequivalence for nearly 30% of generics in each of studied INN.

Scientifically well-founded use of this accessible, easily feasible and reproductible method permits reduction of financial costs for bioequivalence proof, that is of current importance for generics used for treatment of prevailing diseases, such as nonsteroid anti-inflammatory, antiviral, antituberculous, antihypertensive and others preparations. Especially because many of them are included into the Health Ministry's Additional Medications Provision/Supply program List and are covered by public funds.

References

1. 14^th WHO Model list of Essential Medicines, Geneva, World Health Organization, March 2005.

2. Pharmacopoeia of the United States. The National Formulary. USP 31/NF 26. - 2008.

3. Anonymous.”Annex 7”: Multisourse (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability. – WHO Technical Report Series, № 937, 2006.

4. Anonymous.”Annex 8”: Proposal to waive in vivo bioequivalence requirements for WHO Model list of Essential Medicines immediate-release, solid oral dosage forms. WHO Technical Report Series, No. 937, 2006.

5. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX., Amidon GL. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol pharm. 2006 Nov-Dec; 3(6):631-43.