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

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

Scored Tablets

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

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.

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%.

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>

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>

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

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

Iran in Zone?! Pharmacist

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

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

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

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

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

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

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

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)

Storage Conditions

“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

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

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

Drug product Exporting Stability studies should perform based on destination zone

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

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.

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