Saturday, January 9, 2010

A Biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (not considered necessary for product approval). Instead of conducting expensive and time consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether the two pharmaceutical products are equivalent. At that time the Biowaiver was only considered for scale-up and post approval changes (SUPAC) to pharmaceutical products.

More recently, the application of the Biowaiver concept has been extended to approval of certain orally administered generic products (www.fda.gov/cder/guidance/3618fnl.htm).

only APIs with high solubility and high permeability and which are formulated in solid, immediate release (IR) oral formulations can be approved on the basis of the Biowaiver procedure. A major advantage of the Biowaiver procedure is the simplification and reduction of time required for product approval, thus reducing the cost of bringing new products to market.

Biopharmaceutics Classification System :

BCS class I: “high” solubility – “high” permeability

• BCS class II: “low” solubility” – “high” permeability

• BCS class III: “high” solubility – “low” permeability

• BCS class IV: “low” solubility – “low” permeability

How is high or low solubility currently defined by HHS-FDA?
The aqueous solubility of a drug substance is considered as high according to the HHSFDA BCS criteria when:
-The ratio of the highest orally administered dose (in mg) to the solubility (mg/ml) is less than 250 ml
-This criterion is met over the pH range 1-7.5 at 37°C
According HHS-FDA guidances, the determination of the equilibrium solubility should be carried out with the shake-flask method (other methods like acid or base titration are permitted, when their ability to predict the equilibrium solubility is justified). The experiments should be carried out a temperature of 37+ 1°C. Further, a sufficient number of pH conditions should be chosen to cover the pH range of 1-7.5 and each determination should be carried out at least in triplicate. The buffer solutions given in the USP are appropriate for the tests, but other buffers are also allowed for the experiments. The pH value of each buffer solution should be checked before and after each experiment. Degradation of the API due to pH or buffer composition should also be reported along with other stability data.
The reason for the 250 ml cut-off criterion for the dose:solubility ratio is that in pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1-7.5), solubility problems are not expected to hinder the uptake of the drug in the small intestine.
The other important parameter for the BCS is the intestinal permeability of the drug.

How is high or low permeability currently defined by HHS-FDA ?
According to HHS-FDA a drug is considered a highly permeable, when more than 90% of the orally administered dose is absorbed in the small intestine.
Permeability can be assessed by pharmacokinetic studies (mass balance studies for example), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models or Caco 2 cell lines or other suitable, validated cell lines. In vivo or in situ animal models or in vitro models (cell lines) are only considered appropriate by HHS-FDA for passively transported drugs. It should be noted that all of these measurements assess the faction absorbed (as opposed to the bioavailability, which can be reduced substantially by first pass metabolism).

Which pharmaceutical formulations can currently be considered for a biowaiver according to HHS-FDA?
In order to be considered bioequivalent according to the HHS-FDA Biowaiver procedure, a pharmaceutical product:
• should contain a class 1 substance

• should be rapidly dissolving, meaning it should release at least 85% of its content in 30 minutes in three different buffers (pH 1.2, pH 4.5 and pH 6.8, composition see multi source document) in a paddle (50 rpm) or basket (100 rpm) apparatus at 37°C and a volume of 900 ml

• should not contain excipients which could influence the absorption of the drug • should not contain a drug with a narrow therapeutic index

• should not be designed to be absorbed from the oral cavity. The reasoning for the above-mentioned dissolution restriction is that when a highly soluble, highly permeable drug dissolves rapidly, it behaves like a solution in the gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is insignificant, provided that excipients which influence the uptake across the gut wall are excluded from the formulation. The API is not prone to precipitation after its dissolution due to its good solubility under all pH conditions likely to be found in the upper gastrointestinal tract. The high permeability assures the complete uptake (> 90%) of the API during its passage through the small intestine. The fast dissolution of the product guarantees that the API is available long enough for the uptake in small intestine (the passage time in the small intestine is approximately 4 hours) and negates any slight differences between the formulations.
Pharmaceutical products containing an API with a narrow therapeutic index should always be tested with in vivo methods, since the risk for the patient resulting from a possible incorrect bioequivalence decision using the Biowaiver procedure is considered too high with these kinds of APIs.
As the BCS is only applicable to drugs which are absorbed from the small intestine, drugs with different sites of absorption (oral cavity) are not eligible for a Biowaiver.
It can be easily seen that the HHS-FDA requirements for classification of APIs and eligibility criteria for the Biowaiver are very strict. In the last decade, several publications and continuing scientific discussions have suggested that the original HHS-FDA criteria for application of the Biowaiver procedure can be relaxed without substantially

WHO high solubility definition
When an API shows a dose/solubility ratio of less than 250 ml at 37°C over a pH range of 1.2-6.8, it can be classified as “highly soluble”. The decrease in pH from
7.5 in the FDA Guidances to 6.8 reflects the need to dissolve the drug before mid-jejunum to ensure enough reserve length for absorption from the GI tract. Furthermore, the dose that is to be used for the calculation is the highest dose indicated in the Model List, even though in some countries other doses may be available on the market.

WHO permeability definition
When an API is absorbed to an extent of 85% or more, it is considered to be “highly permeable”. The permeability criterion was relaxed from 90% in the FDA Guidances to 85% in the WHO multisource document. Some examples of APIs now included in BCS class I that were previously considered to be Class III are: paracetamol, acetylsalicylic acid, allopurinol, lamivudine, promethazine.
Application of these revised criteria has changed the classification of some APIs in the list. Thus, the classifications in the tables attached to this document supercede those in previous publications. As new APIs on the Model List, it will be necessary to classify these according to the revised BCS, so it is anticipated that the Tables will be revised regularily. In addition, some APIs have not yet been sufficiently characterized to assign a BCS classification. As the Tables evolve, it is anticipated that more concrete information will be generated for these APIs as well.
The potential impact of the revised guidelines on registration requirements to establish interchangeability is that a large number of medicines on the EML could become eligible for approval based on in vitro bioequivalence testing in accordance with the dissolution tests prescribed in Section 9 of the Multisource document.

WHO ADDITIONAL CRITERIA FOR APPLICATION OF THE BIOWAIVER PROCEDURE
For all APIs on the EML, it is imperative to consider not only the physical and absorption properties of the API when evaluating the API for Biowaiver, but (as outlined in the Multisource document) to perform a benefit/risk analysis in view of usage at the national level. As an example, in some countries amoxicillin is used primarily for ambulatory patients with mild to moderate upper respiratory tract, urinary tract and other infections. In other countries, amoxicillin might also be used for severe or even life-threatening infections, in which case the risk to the patient of arriving at the wrong bioequivalence decision would be far greater.
Thus, the eligibility criteria according to WHO are
1. The BCS classification (according to the revised criteria) of the API.

2. Risk assessment: Only if the risk of an incorrect biowaiver decision and an evaluation of the consequences (of an incorrect, Biowaiver-based equivalence decision) in terms of public health and individual patient risks outweighed by the potential benefits of the Biowaiver approach should the Biowaiver procedure be applied.

3. Dissolution requirements for the pharmaceutical product: -Very rapidly dissolving (release of >85% of the labelled amount of drug in 15 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed of 75 rpm in the paddle apparatus or 100 rpm in the basket apparatus (applies to pharmaceutical products containing Class III APIs).
-Rapidly dissolving (release of >85% of the labelled amount of drug in 30 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed of 75 rpm in the paddle apparatus or 100 rpm in the basket apparatus (applies to pharmaceutical products containing Class I APIs and Class II APIs

4. Excipient considerations

The national authority should be mindful that some excipients can influence motility and/or permeability in the gastrointestinal tract. Therefore, the excipients used in the multisource product formulation should be scrutinized. In this regard, the national authority can draw on the experience of formulations which have been approved on the basis of human bioequivalence studies in their own or in other jurisdictions.
If the multisource product under consideration contains excipients that have been used before in similar amounts in other formulations of the same API, it can be reasonably concluded that the excipients will have no unexpected influence on the bioavailability of the product. If, however, the formulation contains different excipients or very different amounts of the same excipients, the national authority may choose not to allow the Biowaiver procedure to be used.
A list of usual and acceptable excipients can be found e.g. at the following website: (
www.fda.gov/cder/iig/iigfaqWEB.htm), formulations of some products can be found on national websites of national drug regulatory authorities.

The decision of a national authority to allow a biowaiver based on the BCS should take into consideration the solubility and permeability characteristics as well as the therapeutic use and therapeutic index of the active pharmaceutical ingredient (API), its pharmacokinetic properties, the similarity of the dissolution profiles of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37°C. Data related to the excipient composition of the multisource product is also required. A systematic approach to the biowaiver decision has been established by the International Pharmaceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences: http://www3.interscience.wiley.com/cgi-bin/jhome/68503813 . They can further be downloaded from the International Pharmaceutical Federation (FIP) website: http://www.fip.org/. These monographs provide detailed information which should be taken into account whenever available in the Biowaiver consideration

BIOWAIVER TESTING PROCEDURE ACCORDING TO WHO
Depending on the BCS classification of the API, based on solubility and permeability characteristics listed in the accompanying Tables, the testing procedure is defined in 9.2.1 of the "Multisource document".


For pharmaceutical products containing BCS class I (highly soluble, highly permeable) APIs:
For rapidly dissolving (as defined above) pharmaceutical products containing BCS class I APIs, greater than 85% dissolution of the labelled amount is required within 30min in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75rpm or alternatively the basket apparatus at 100rpm. The dissolution profiles of the comparator and the multisource products should be compared by an f2 > 50 or an equivalent statistical criterion.
If after 15 min more than 85% are released from the comparator and the multisource formulation under the above-mentioned conditions the product will be considered very rapidly dissolving. In this case the products are deemed to be equivalent and a profile comparison is not required.


For pharmaceutical products containing BCS class III (highly soluble, low permeability) APIs:
A biowaiver can be only considered if both the multisource and the comparator product are very rapidly dissolving; 85% or more dissolution of the labelled amount of the API should be achieved within 15min in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75rpm or alternatively the basket apparatus at 100 rpm.
Generally the risks of an inappropriate biowaiver decision should be more critically reviewed (side specific absorption, induction/competition at the absorption side, excipient composition and therapeutic risks, etc.) than for BCS class I drugs.
For pharmaceutical products containing APIs with high solubility at pH 6.8 but not at pH 1.2 or
4.5 and with high permeability (by definition, BCS class II compounds with weak acidic properties): These are eligible for a Biowaiver provided that the multisource product:
(i) is rapidly dissolving i.e. 85% or more dissolution of the labelled amount of the API should be achieved within 30 min in standard media at pH 6.8 using the paddle apparatus at 75 rpm or alternatively the basket apparatus at 100rpm, and (ii) The multisource product exhibits similar dissolution profiles, as determined with the f2 value or equivalent statistical evaluation, to those of the comparator product in buffers at all three pH values (pH 1.2, 4.5 and 6.8). For multisource products containing Class 2 APIs with dose:solubility ratios of 250 ml or less at pH 6.8, the excipients should additionally be critically evaluated in terms of type and amounts of surfactants in the formulation.
BCS Dissolution test
Essential Medicines dosage form aluminium hydroxide 500mg N.R. N.A. antacid local effect amiloride hydrochloride 5mg high high 1 9.2.1.1 diuretic

amitriptyline hydrochloride 25mg1 high high 1 9.2.1.1 psychotherapeutic medicine

amlodipine 5mg high high 1 9.2.1.1 antihypertensive medicine Druga Medicines Lista Solubilityb Permeabilityc classd (for biowaiver)e Potential risksf List (EML)g indicationsa
abacavir 200mg high low 3 9.2.1.2
antiretroviral unknown whether poor BA is due to poor solubility or
antiglaucoma poor solubility and acetazolamide 250mg low low 4
no biowaiver
medicine permeability NSAID, antimigraine acetylsalicylic acid 500mg high high 1 9.2.1.1
medicine antithrombotic acetylsalicylic acid 100mg high high 1 9.2.1.1
medicine

aciclovir 200mg high low 3 9.2.1.2
antiherpes medicines chewable tablet; unknown whether poor BA is due to poor solubility

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Hyderabad, Andhra, India
working as a clinical Research coordinator at yashoda Hospital,Somajiguda,Hyderabad

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