לש םינקתו תרוקיבל ןוכמה...the transfer of molecules or ions from solid state in...

עמליה לוי ' דר

מעריכת תיקים כימיה המכון לביקורת ותקנים של

חומרי רפואה

יום עיון בנושא רישום תכשירים

21.11.17

Dissolution testing is a requirement for all solid oral dosage in all phases of development for product release and stability testing .

It is a key analytical test used for detecting physical changes in an active pharmaceutical ingredient (API) and in formulated product.

Amalia.levy@moh.gov.il

The transfer of molecules or ions from solid state in solution is known as dissolution.

Dissolution and drug release tests are in-vitro tests that measure the rate and extent of dissolution or release of the drug substance from a drug product, usually in an aqueous medium under specified conditions

In the pharmaceutical industry, it may be defined “the amount of the drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature

and solvent composition.

to guide development of new formulations; to assist in proper formulation selection (selection of excipients) and to optimize

the manufacturing process (e.g., compression forces, equipment) during dosage form optimization;

to assess the batch to batch quality of a drug product; to compare new or generic formulations with an existing product; to assess the stability of the drug product, helping in establishment of shelf life; to ensure the product quality in case of certain scale-up and post approval changes

(SUPAC) like manufacturing site changes, increase or decrease of batch size and small quantitative changes in excipients;

to provide a basis for achieving an in vitro/in vivo correlation (to predict product performance in vivo);

to minimize the need for bioequivalence studies (Biowaiver)

Amalia.levy@moh.gov.il

The specific dissolution technique employed is determined by the dosage form characteristics and the intended route of administration. For solid dosage forms, industry standard dissolution testing methodologies are USP or EP apparatus.

Amalia.levy@moh.gov.il

pH Dissolution media

pH 1.0 HCl

pH 1.2 NaCl, HCl

pH 1.5 NaCl, HCl

pH 4.5 Phosphate or acetate buffer

pH 5.5 and pH 5.8 Phosphate or acetate buffer

pH 6.8 Phosphate buffer

pH 7.2 and pH 7.5 Phosphate buffer

In general an aqueous medium is used. The pH of dissolution medium is usually set between pH 1 and pH 8. In specific cases, when justified , the media may contain enzymes, surfactants, etc.

Amalia.levy@moh.gov.il

900mL, 500mL (for low dosage strengths) 1000mL, 2L or 4L for increase sink 200mL or smaller volumes (as justified)

When developing a dissolution procedure, one goal is to have sink conditions, which are defined as having a volume of medium at least three times the volume required to form a saturated solution of drug substance.

37°C±0.5°C

Amalia.levy@moh.gov.il

Basket • 50-100rpm Paddle • 50 rpm (preferred for BCS) • 75 rpm ( to eliminate coning) • 25 rpm (for suspensions) • 100rpm (needs justification for IR, common for ER)

• 10 ,20 ,30, 45, 60 min

At set time points aliquots of filtered medium are removed and analyzed for API content by HPLC or UV-VIS.

Amalia.levy@moh.gov.il

mL.1000 Phosphate buffer; 6.8 pH : Medium rpm. 100 : 1 Apparatus

Time: 30 minutes. Procedure—Determine the amount of C17H21NO3 dissolved from UV absorbances at the wavelength of maximum absorbance at about 274 nm of filtered portions of the solution under test, suitably diluted with Dissolution Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Etodolac RS in the same Medium. Tolerances—Not less than 80% (Q) of the labeled amount of C17H21NO3 is dissolved in 30 minutes

Amalia.levy@moh.gov.il

Fr

Conventional-release dosage forms In most cases, when tested under reasonable and justified test conditions,

per cent of the active 80are that at least 1Sthe acceptance criteria at level . This min or less 45substance is released within a specified time, typically

-.2.9.3, since, as referred to in Table per cent 75value of Qcorresponds to a 1, for level S1 the individual value of each of the 6 units tested is not less than Q + 5 per cent, i.e. not less than 80 per cent. Typically, a single-point acceptance criterion is sufficient to demonstrate that the majority of the active substance has been released, although in certain circumstances it may be necessary to test at additional time point(s), in order to demonstrate adequate dissolution.

Amalia.levy@moh.gov.il

Stage Number Tested Acceptance Criteria

S1 6 Each unit is NLT Q + 5%.

S2 6 Average of 12 units (S1 + S2) is ≥Q,

and no unit is <Q − 15%.

S3 12

Average of 24 units (S1 + S2 +S3) is ≥Q,

NMT 2 units are <Q − 15%,

and no unit is <Q − 25%.

Amalia.levy@moh.gov.il

1. Physicochemical properties of drug substance 2. Factors related to drug product formulation 3. Factors Relating Dissolution Apparatus 4. Factors Relating Dissolution media

Amalia.levy@moh.gov.il

1. Physicochemical Properties of Drug Substance Drug Solubility: Solubility of drug plays a prime role in controlling in dissolution from dosage form.

:Particle size There is a direct relationship between surface area of drug and its dissolution rate. Since, surface are increase with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size. Polymorphism: The polymorphic forms of drugs have shown to influence changes in the solubilizing characteristics and thus the dissolution rate of the drug substance. Amorphous forms of drug tend to dissolve faster than crystalline materials. Ionic Status: Base, acid or salt identity of the counter ion. For instance: calcium salt, or magnesium salt of atorvastatin.

Amalia.levy@moh.gov.il

2. Factors related to drug product formulation A variety of factors concerning the formulation of a drug product can directly influence the dissolution rate of the active ingredient contained within it. Once these factors are completely characterized, one can use this information to achieve custom-tailored drug dissolution profiles. This information is then employed in the development of optimally effective dosage forms.

3. Factors Relating Dissolution Apparatus Size and shape, stirring device, vibrations and alignment of the stirring element.

4. Factors Relating Dissolution test parameters pH of dissolution media and temperature.

Amalia.levy@moh.gov.il

All relevant applications (new chemical entities & generics) • Dissolution method development. • Description and justification of any changes (dissolution method,

dissolution results, formulation, manufacture) through development. • Dissolution method validation. • Dissolution data within batch analyses and stability studies. • Comparison of strengths.

Generic Comparison to reference medicinal product (mean of n=12, RSD). Biowaivers for multiple strengths for proportional formulations. BCS Biowaivers (in the future).

Amalia.levy@moh.gov.il

Paddle, 75 (or 50) rpm

Basket, 100rpm

Apparatus

((Choice

1. pH 6.8 phosphate buffer

2. pH 4.5 acetate buffer

3. Buffer pH 1.2 or 0.1M HCl

4. Release medium (if different )

Dissolution media

(All three media for full

comparison)

900 mL or less Volume of media

37oC ± 0.5oC Temperature

5, 10, 15, 20, 30, 45, 60 min Sampling points

12 Units

Amalia.levy@moh.gov.il

https://www.accessdata.fda.gov/scripts/cder/dissolution/

Drug Name

Dosage Form

USP Apparatus

Speed (RPMs)

Medium Volume

(mL) Recommended Sampling

Times (minutes) Date

Updated

Cinacalcet HCl

Tablet II (Paddle) 75 0.05 N HCl

900 10, 20, 30 and 45 01/26/2006

קרוב לוודאי זו , הינם פר פורמולציה מסוימתDissolution -חשוב לזכור כי תנאי ה

.ב"הרשומה בארהעל , אחרת פארמקופיאליתאו שיטה FDA-על פי ה Dissolutionבמידה וקיימת שיטת

.ובמקרה ואיננו מאמץ אותה עליו להצדיק מדוע, יצרן התכשיר להתייחס לשיטה זו

.פארמקופיאליתגם אם היא דיסקרימינטיביתיש להוכיח כי השיטה

For instance:

Amalia.levy@moh.gov.il

The discriminatory power of the dissolution method is the method's ability to detect changes in the drug product. Demonstrating the discriminatory power of the dissolution method it is both challenging and important, particularly in monitoring API or formulation parameters critical for optimal product performance of the poorly soluble compound. A dissolution method that is capable of distinguishing significant changes in the composition and manufacturing process is defined a discriminative method.

Amalia.levy@moh.gov.il

Classification system for APIs • Aqueous solubility • Intestinal permeability

Amalia.levy@moh.gov.il

In the context of this reflection paper IR is identified as at least 75% (Q) of the active substance is dissolved within 45 minutes.

This paper discusses the suitability of the dissolution method and the specifications for in vitro dissolution of orally administered generic drug products with immediate release characteristics .

The discriminatory power is the ability of a test procedure to discriminate between batches manufactured with different critical process parameters and /or critical material attributes which may have an impact on the bioavailability.

Demonstrating discriminatory power: To achieve this, batches with meaningful changes compared to the applied finished product should be manufactured.

Setting Specifications (decision tree).

Amalia.levy@moh.gov.il

.כדיסקרימינטיביתלא הוכחה Dissolution -שיטת ה•

עדין יש להוכיח את היכולת פארמקופיאליתבמידה והשיטה היא •

. Dissolution -של שיטת ה הדיסקרימינטיבית

כאשר החומר הפעיל הוגדר dissolution-של שיטת ה דיסקרימינטיביותהוכחת •

ידי הורדה של אחד מחומרי העזר ולא על ידי שינוי בכמות חומרי -על BCS I, III -כ

.העזר

וכי החומר הפעיל מסיס מאד ולכן לא BCS I, III-הטענה כי החומר הפעיל שייך ל•

של השיטה ואין צורך לבצע ניסוי להוכחת דיסקרינימטיביותניתן להוכיח

.הדיסקרימינטיביות

דקות כאשר התכשיר 45 -ב 75% (Q)ספציפיקציה של קביעת •

ואז גם אם אצווה לא תקינה לא יהיה very rapidly dissolvedהוא

.ניתן לזהות זאת

.הפיזיולוגים pH -מחוץ לטווח ה Dissolutionשיטת קביעת •

-הבין תכשיר גנרי לתכשיר הייחוס וערך במידה ונעשה מבחן ביו •

f2 (similarity factor במבחן ההתמוססות ההשוואתית ) מקטן-

.צורך להסביר את חוסר ההתאמהיש , 50

לתכשיר הגנרי אינה היחוסהשוואתית בין תכשיר בדיקת מסיסות •

.המקובלים pH -ה 3על כל מבוצעת

מבצעים את ( למשל בבקשות לשינוי)בבדיקת מסיסות השוואתית •

. טבליות 12טבליות ולא על פי המפורט קרי 6הבדיקה עבור

.גבוה מהמקובל ללא הסבר (rpm)שימוש במהירות סבוב •

אין הצגה של התוצאות המספריות בנוסף Dissolution-במבחני ה•

.לגרפים

1. EP 9th edition, 2.9.3 Dissolution Test for Solid Dosage Forms 2. EP 9th edition, 5.17.1 Recommendations on Dissolution testing 3. USP 40th edition < 711 > <1092> <724> 4. Dissolution Testing and Specification Criteria For Immediate –

Release Solid Oral Dosage From Containing Biopharmaceutics Classification System Class 1 and 3 Drugs (August 2015)

5. Guideline on The Investigation of Bioequivalence 6. Reflection Paper on the Dissolution specification for generic

oral immediate release products (August 2017) 7. https://www.accessdata.fda.gov/scripts/cder/dissolution/ 8. Guidance for Industry Dissolution Testing of Immediate Release

Solid Oral Dosage Forms. 9. CPMP/EMP/QWP/1401/98 Rev.1/Corr

תודה על ההקשבה