QUALITY ASSURANCE AND QUALITY CONTROL

CURRENT GOOD MANUFACTURING PRACTICE

- Not a sole responsibility of QC group but also of the production group - Permits the use of precision automatic, mechanical or electronic equipment in the

production and control of drugs when adequate inspection and checking procedures are used to assure proper performance

OBJECTIVE OF cGMP:
1. Safe 2. Pure 3. Effective

Non-compliance---contamination, mixups and errors

QUALITY ASSURANCE
- sum total of the organized arrangements

made with the object of ensuring that products will be consistently of the quality required by their intended use

QUALITY CONTROL
Part of cGMP concerned with sampling,

specifications, testing, organization, documentation and release procedures

Quality Assurance vs. Quality Control

Quality Assurance Quality Control

An overall management plan to guarantee the integrity of data (The system)

A series of analytical measurements used to assess the quality of the analytical data (The tools)

STANDARDS AND SPECIFICATIONS

a. FORMULA - concise and precise statement of the ingredient that comprise the product, with % /weight of each b. RAW MATERIAL SPECIFICATIONS - enumerate characteristics of all materials that go into the product and the permissible range of purity of each ingredient

c. STANDARD OPERATING PROCEDURE - step by step method on how to go about the job d. FINISHED PRODUCT SPECIFICATION - cover all characteristics that affect the proper performance, purity, safety and stability of the product

e. PACKAGING MATERIAL STANDARD - set for everything that goes around the product f. TESTING METHODS - Testing procedures to that they yield results of comparable precision and accuracy

DEFECTS
- Undesirable characteristic of a product - Failure to confirm to conformance

DEFECTIVE -unit of a product which contains one or more defects

ACCDG. TO MEASURABILITY
a. VARIABLE DEFECT
Measured directly by instruments giving dimension of length, weight, height, thickness etc. b. ATTRIBUTE DEFECT - cannot be measured directly by instruments - odor or visual examination like color, clarity, cleanliness, smoothness etc.
-

ACCORDING TO SERIOUSNESS OR GRAVITY

1. CRITICAL DEFECT - a defect which may endanger life or property and may render the product nonfunctional 2. MAJOR DEFECT - defect which may affect the function of the object and therefore, may render the product useless

3. MINOR DEFECT - defect which does not endanger life or property nor will it affect the function but nevertheless remains a defect since it is outside the prescribed limits

ACCORDING TO NATURE
1. OCULAR DEFECT - defect that is visible 2. INTERNAL DEFECT - defect which is not seen although present 3. PERFORMANCE DEFECT - defect in function

SOURCES OF VARIATION
SOURCE/S MATERIALS EXAMPLE/S -Between suppliers of same substances -Between batches from same supplier -Variation within a batch -Variation of equipment for the same process -Difference in adjustment of equipment -Aging and improper care -Inexact procedures -Inadequate procedures -Negligence by chance -Improper working conditions -Inadequate training, and understanding -Dishonesty, fatigue and carelessness

MACHINES

METHODS

MEN

QUALITY CONTROL ORGANIZATIONAL CHART

Quality Control Manager Materials Inspection Section

Analytical Laboratory
Biological Testing Laboratory

Specifications and Analytical Development

Quality Coordinating Office

CONTROL FUNCTIONS
a. Analysis Function b. Monitor Function c. Record Review and Release Function d. Audit Function

TERMS:
a. ACCURACY- closeness of test results to the TV

b. PRECISON- degree of agreement among individual test results when the method is applied repeatedly to multiple samplings of a homogenous sample c. SPECIFICITY- ability to assess unequivocally the analyte in the presence of components such as: impurities, degradation pdts. d. ROBUSTNESS- measure of its capacity to remain unaffected

TABLETS:
HARDNESS EQUIPMENTS Stokes hardness tester (Monsanto) Strong Cobb hardness tester Pfizer tester Erweka tester Schleuniger

ACCEPTANCE HARDNESS RANGE 4-10 Kg(ordinary compressed tab) 2 Kg (Sublingual & chewable tab) 10 Kg (Buccal & extended/modified release tab) THICKNESS EQUIPMENT ACCEPTANCE CRITERIA Micrometer caliper 5 % of set std. thickness

FRIABILITY EQUIPMENT Roche friabilator Setting: 25 rpm Time: 4 mins. (100 revolutions)

ACCEPTANCE CRITERIA STAGE/SAMPLE 1( 10/20) 2(20/40) New formulation ACCEPTANCE LIMIT NMT 1 % NMT 1 % (Average of 3 trials) NMT 0.8 %

DISSOLUTION TESTING

Media Temperature Equipment

Procedure

37 2 C ( 35-39 C) Basket Rack Assembly

Load 1 tablet or capsule in each of the tube and expose the product into the conditions specified. Overlay with sinker or 10 mesh wire cloth(as specified) Plain, coated tablet and capsules: -30 mins (H2O) Enteric coated tablet: 5 mins soaking(H2O) 1 hr(simulated gastric juice) 1 hr(simulated intestinal juice) Buccal tablets: 4 hrs(H2O) Sublingual tablets: 3 mins (H2O) Passed test- if none remained on the wire If 1 or 2 did not disintegrate, perform 2 trials NMT 2 of the 18 samples tested failed to disintegrate

Time requirement

Criteria

DISSOLUTION TESTING

Media Temperature Apparatus

37 0.5 C ( 36.5-37.5C) Consist of a vessel with cover, motor, H2O bath maintained at ( 37 0.5 C) metallic drive shaft Type 1: Basket accessory Type 2: Paddle accessory Stage 1: 6 samples Each unit should at least Q + 5 % **Q- % accdg. to label claim Stage 2: + 6 samples Average of 12 units is Q & no unit is < Q-15% Stage 3: + 12 samples Average of 24 units is Q & NMT 2 units are < Q-15 % & no unit is < Q25%

Criteria

Formulas:
Abs(sample) x Conc. (std) x dilution factor Abs(standard)

% label claim = -------------------------- x 100

Label claim

Average weight Adjusted Label claim= % Label claim x --------------------------Weight (sample)

WEIGHT VARIATION TESTING & CONTENT UNIFORMITY TEST

CONTENT UNIFORMITY TEST -For tablets containing 50 mg or less of an active ingredient -Ensures potency of tablet products -USP limit: 85-115 % -Sample: NLT 30 tablets then assay 10 tablets individually - For tablets containing 50 mg or more of an active ingredient

WEIGHT VARIATION TESTING

ACCEPTABLE TABLET WEIGHT VARIATIO N

< 130 mg 130- 324 mg > 324 mg

% VARIATION
10 % 7.5 % 5%

SOLUTIONS, SUSPENSIONS, EMULSIONS & GRANULES

a. SOLUTIONS: - appearance - Stability - Chemical - Physical(viscosity, color, clarity, odor & taste)

b. SUSPENSIONS:
- Sedimentation volume - Redispersability - Particle size measurement - Rheological properties - Temperature and gravitational stress

c. EMULSIONS:
- Tests for creaming, cracking, phase

separation and phase inversion - Particle size nos. analysis

d. GRANULES:
Particle size distributions Angle of repose Bulk density Moisture content Content uniformity Shape TECHNIQUES: - Sieving - Optical microscopy - Adsorption study - Light scattering technique - Sedimentation
-

ANGLE OF REPOSE:
ANGLE OF REPOSE
< 25

INTERPRETATION
Excellent

25-30
30-40 >40

Good
Fair (+ glidant) Poor

ANIMAL USED IN TESTING OF DRUGS:

DRUG
DIGITALIS GLUCAGON INJECTION

ANIMAL EMPLOYED
Pigeon Cat

OXYTOCIN INJECTION
PARATHYROID INJECTION HEPARIN AND PROTAMINE SULFATE VASOPRESSIN INJECTION

Chicken
Dog Sheep blood plasma Male rat

SAMPLING AND SAMPLING PLAN

INSPECTION STEPS: 1. Interpretation of the specification 2. Measurement of the product 3. Comparison of the product with specification 4. Judgment as to conformance 5. Disposition of the product 6. Recording of the data obtained

SAMPLING
- Process of removing an appropriate number of items from a population in order to make

inferences to the entire population

POPULATION - is the totaling of all actual or conceivable items of a certain class under considerations

SAMPLE
- A finite number of objects selected from a

population RANDOM SAMPLE - chosen such that one object has a good chance of being selected as another

MATERIALS TO BE SAMPLED
a. Raw materials b. Packaging and printed materials c. Intermediate products d. Final products (before, during and after packaging operations)

SAMPLING PLAN
- a definite working rule regarding size and
frequency of sample and the basis for acceptance or rejection; RECEPTION QUARANTINE- yellow REJECTED- red APPROVED- green

PACKAGING MATERIALS:
a. Primary packaging- direct contact with the product itself b. Secondary packaging- not come in direct contact with the product and serve as accessory to the primary packaging

REASSAY DATES
- Date of retest - Periodic testing--done to revalidate material

MANUFACTURING CONTROL
MASTER FORMULA RECORD - original document used as key in the production of products BATCH LOT BATCH NUMBER/LOT NUMBER/CONTROL NUMBER

STABILITY
- Ability of a particular formulation in a specific container to remain within its physical, chemical and toxicological specifications

STABILITY STUDIES
STABILITY STUDY STORAGE CONDITIONS MINIMUM PERIOD COVERED

Long-term

25 2C

60 5 % RH

12 months

Intermediate
Accelerated

30 2 C
40 2 C

60 5 % RH
75 RH

8 months
5 months

WORLD CLIMATE CONDITIONS:

CLIMATE CONDITIO NS Mean Annual Temp (C) Kinetic Mean Temp (C) Mean Annual RH ( %) ZONE I (Temperate) 20.5 ZONE II (Mediterranea n/ Subtropical) 20.5-24 ZONE III (Hot, Dry) ZONE IV (Hot, Humid/ Tropical) 24

24

21

26

31

31

45

60

40

70

SAMPLE PROBLEMS:
**STABILITY COMPUTATIONS: FORMULATION:
ACTIVE 1 65 mg (limits:95-105%)

ACTIVE 2

15 mg (limits: 90-110%)

ACTIVE 3

122 mg (limits: 90-110%)

Results of analysis:
Initial 3 mos. 6 mos. 12 mos.
67 14.94 126 66.80 14.90 124.10 65.40 14.21 117.76

24 mos.
63.06 14.01 113.30

36 mos.
61.98 13.67 110.60

48 mos.
61.79 13.38 109.50

Active 1 67.00 Active 2 Active 3 15.00 128.30

Questions:
1. Determine the minimum and maximum

limits of each active based on the specifications. 2. What is the shelf life of the formulation? 3. What would be the expiry date of a product manufactured on December 22, 1994? ----more problems.try to solved plstnx

2. Assay of 250 ml solution of Dopamine 200 mg injection resulted in the following data. Based on these, determine the amount of Dopamine in 100 ml solution.
Sample Volume: 5 ml Solution Volume: 250 ml Absorbance (sample): 38259 Absorbance (standard): 20163

FORMULA:
Absorbance(sx) 100 1

Concn (mg/ml) = ---------------------x---------- x ---Absorbance(std) Volm(sx) 1000

THANK YOU!!!GODBLESS