1. Physico-chemical Control of Dosage Forms
Dr. Zahra Hesari
Pharm D, PhD of Pharmaceutics
Faculty of Pharmacy,
Guilan University of Medical Sciences
Pharmacist

2. Review Monograph tests Uniformity of Dosage Unit Disintegration
Dissolution
Drug Release
Dietary Supplements

3. Scored Tablets

4. Functionally scored tablets
<705> QUALITY ATTRIBUTES OF TABLETS LABELED AS HAVING A FUNCTIONAL SCORE
Functionally scored tablets
Exact dose adjustment for patients
Each split portion are expected to conform to the quality attributes of the whole tablets.
Splitting Tablets with Functional Scoring and Dissolution or Disintegration

5. SPLITTING TABLETS WITH FUNCTIONAL SCORING
Test Procedure:
Take a random sample of 30 intact tablets, and proceed as follows.
Accurately weigh each tablet, and record its weight.
For each intact tablet, determine the expected weight of the split portions by dividing the whole-tablet weight by the designated number of split portions indicated on the labeling.
Split each tablet by hand (without mechanical assistance) into the designed number of split portions, and weigh each split portion.
For each tablet, determine the percent of the expected weight in each split portion.
Each split portion has NLT 75% and NMT 125% of
the expected weight of the split tablet portion
Acceptance criteria: NL T 28 of the 30 tablets are acceptable.

6. DISSOLUTION
Use split portions from tablets that are acceptable according to the Splitting Tablets with Functional Scoring test.
Immediate-Release Tablets
S2 stage (Dissolution <711>)
Test 12 split tablet portions according to the specified Medium, Apparatus, Times, and Analysis.
The average of the 12 results is NLT Q, and no result is less than Q- 15%.

7. Extended-Release Tablets Procedure 1&2 Procedure 2:
Procedure for Extended-Release Dosage Forms, Dissolution <711>
Use a split-tablet portion as the dosage unit.
Individually test 12 dosage units.
Medium, Apparatus, Times, and Analysis: As given in the monograph following the appropriate test number found on the labeling.
Acceptance criteria: The percentages of the labeled amount released at the times specified conform to the L2 level criteria of Acceptance Table 2 in <711>

8. DISINTEGRATION
When used as a surrogate for dissolution testing as specified in the monograph
Use split portions from tablets that are acceptable according to the Splitting Tablets with Functional Scoring test as the dosage unit
Disintegration <701>

9. Stability Studies
ICH stands for International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use
Harmonization of registration applications within the three regions of the EU, Japan and the United States.
Q1A(R2): Stability Testing of New Drug Substances and ProductsQ1A
Q1B: Photostability Testing of New Drug Substances and Products
Q1C: Stability Testing for New Dosage Forms
Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
Q1E: Evaluation of Stability Data
Pharmacist

10. Mean Kinetic Temperature (MKT) in Stability Studies
Instability factors:
Humidity
Light
Temperature
Temp behavior in country
From the 1st day of the year
Pharmacist

11. Iran in Zone?!
Pharmacist

12. Long term Stability Studies
MKT
Zone 1: 20 °C
Zone 2: 22 °C
Zone 3: 27.9 °C
Zone 4: 27.4 °C
Long term Stability Studies
Pharmacist

13. Accelerated Stability Studies
What’s the concept?
Expiration date extension
Expiration date balance

14. Stress Testing Conditions: Purpose: Light Temperature (80-90’C) pH
Drug substance & Drug product
Development phase
Conditions:
Light
Temperature (80-90’C) pH
Catalysts, oxidants, ions
Purpose:
Decomposition products
Decomposition pathway
Stability indicating method
Pharmacist

15. Stability indicating method
Methods in pharmacopeia & articles
Sophisticated methods vs simple methods
Pharmacopeia: Range of impurities
Pharmacist

16. Formal Stability Testing
Long term (Real time) (Determination of Exp date)
Intermediate
Accelerated (prediction of Exp date)
12 month
Pharmacist

17. Stability Protocols in QC
Selection of batch:
Drug substance:
3 primary batches
minimum of pilot scale
Drug product:
Two of the three batches should be at least pilot scale batches and the third one can be smaller
using different batches of the drug substance
each individual strength and container size of the drug product
Container Closure System
same as or simulates the packaging proposed for storage and distribution, marketing
any secondary packaging and container label
Pharmacist

18. Specification physical, chemical, biological, and microbiological
List of tests
Proposed acceptance criteria
ICH Q6A and Q6B
physical, chemical, biological, and microbiological
Identification, assay, purity, pH, …
Dissolution, disintegration,…
preservative content (e.g., antioxidant, antimicrobial preservative)
functionality tests
stability-indicating analytical procedures
Susceptible to change during storage
Influence quality, safety, and/or efficacy

19. Testing Frequency Long term Accelerated Intermediate
every 3 months over the first year
every 6 months over the second year
annually thereafter
Accelerated
minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months)
Intermediate
minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months)

20. Storage Conditions

21. “Significant change” criteria:
1- A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;
2- Any degradation product’s exceeding its acceptance criterion
3- Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions;
4- Failure to meet the acceptance criterion for pH
5- Failure to meet the acceptance criteria for dissolution for 12 dosage units

22. Impermeable containers
Like ampoules
no concern for
sensitivity to moisture or
potential for solvent loss
microbiological stability
semi-permeable containers
potential water loss (sedimentation)
Physical (moisture absorption in powders), chemical, biological

23. Expiration Date Determination
Long term X=month
Accelerated 6 month
If there is no significant change in Acc:
Exp date=2X if ≤ X+12
For Insulin:
Exp date=1.5X if ≤X+6
Example: X=15
2X= 30 months
X+12=27 months
Example: X=24
1.5X= 36 months
X+6=30 months
Example: X=12
1.5X= 18 months
X+6=18 months

24. Drug product Exporting
Stability studies should perform based on destination zone

25. Reduced Designs Each potency (3 pilot batches)
Each container size (3 pilot batches)
Bracketing
capsules of different strengths made with different fill plug sizes from the same powder blend
tablets of different strengths manufactured by compressing varying amounts of the same granulation
oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants, flavourings).
same container closure system where either container size or fill varies

27. Reduced Designs Matrixing
capsules of different strengths made with different fill plug sizes from the same powder blend,
tablets of different strengths manufactured by compressing varying amounts of the same granulation,
oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants or flavourings).
The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

30. Thank you