Module 1 & 2: Quality Control & Quality Assurance

Quality

• Totality of characteristics or features of a product that bear on its capacity to satisfy stated or implied needs

Quality Assurance

• Sum total of the organized arrangements made w/ the object of ensuring that products will be consistently of the quality required by their intended

Good Manufacturing Practice (GMP)

• Ensure that production consistently produced & controlled according to quality standards & marketing authorization (from FDA)

Quality Control

• Part of GMP concerned with sampling, specifications & testing, & with the organization, documentation & release procedures which ensures that the relevant & necessary tests are intact & in fact carried out & that materials are not released

QA Department Function

• Assures policies are followed inept to economic issues associated with manufacturing & distribution of product

• Cooperate with regulatory agencies & final authority for product acceptance or rejection

QA Department Function

• Helps to identify & prepare necessary SOP’s relative to control of quality

1. Personnel

2. Procedure

3. Equipment

4. Premises

5. Environment

6. Package

7. Starting Materials

8. Validate Processes

Factors Affecting Quality Products (8)

Monograph

• A document which specifies all the tests to be conducted on a particular material or product, the procedure and/or appropriate references containing the details of the procedure and expected results

• Validated by researchers

Certificate of Analysis

• A document containing the result of all tests conducted on a particular material or product to show compliance or non-compliance with established standards or specifications approved by responsible personnel

1. Absolute Error

2. Relative Error

2 Types of Error

Absolute Error

• Distinction between quantities of measured value and actual value

1. Indeterminate (uncontrollable causes)

2. Determinate (identifiable systematic errors or bias)

2 Types of Absolute Error

Indeterminate

• random errors 

• slight variations in a series of observations made by the same observer 

• intangible, elimination by analyst is hard  

• difficult to detect 

• difference of judgment of analyst

Determinate

• Errors by analyst 

• methodological errors 

• instrumental error 

Accuracy

• Closeness of the data to true value

Precision

• Closeness of data

Specificity

• Assess unequivocally the analyte in the presence of components that may be expected to be present

Sensitivity

• Refers to the ability of a test to detect very small amounts of a target analyte (the minimum detectable concentration)

Robustness

• Measure of capacity to be unaffected by small but deliberate variations in method & provides indication of its reliability during normal usage

1. Measurability

2. Seriousness or Gravity

3. Nature

3 Category of Defects

1. Variable Defect

2. Attribute Defect

2 Defects under Measurability

Variable Defect

• Can be measured directly by instruments

• Confiable

Attribute Defect

• Cannot be measured directly by instruments

• Non confiable

1. Critical Defect

2. Major Defect

3. Minor Defect

3 Defects under Seriousness and Gravity

Critical Defect

• May endanger life or property & may render the product non-functional (Absence of Warning)

Major Defect

• May affect the function of the object, & therefore, may render the product useless. (Crack in a Bottle) 

Minor Defect 

• Does not endanger life or property but remains a defect. (Slight deviation of the color of the label from the color standards)

  • Ex: packaging

1. Ocular Defect

2. Internal Defect

3. Performance Defect

3 Defects under Nature

 Ocular Defect

• Visible (Foreign particulate contamination)

Internal Defect

• Not seen although present (Subpotent Drug Product)

Performance Defect

• Defect in function (Suppository that does not melt at body temperature) 

Materials

• Variation between suppliers of same substance 

• Variation between batches from same suppliers 

• Variation within a batch

Machines

• Variation equipment for the same process 

• Difference in adjustment of equipment 

• Aging & improper care

Methods

• Inexact procedure 

• Inadequate procedures 

• Negligence

Men

• Improper working conditions 

• Inadequate training, & understanding 

• Dishonesty, fatigue & carelessness  

Confidence Interval

• range of value around an actual result w/ which true value is expected 

Significance Test

• compare individual values or set of values for significant differences. 

• Null Hypothesis there is no significant differences 

• Alternate Hypothesis

One Tailed

• there is a significant difference & indicates what is the dissimilarities or variations

Two Tailed

• there is a significant difference but doesn’t indicate the dissimilarities or any variations.

Quality Control Testing Of Pharmaceutical Dosage Forms

• sum of all processes done to ensure that product possesses, ensuring its efficacy & safety.

1. Packaging

2. Identity Test

3. Limit Test

4. Potency Test

5. Dosage- Form Specific Test

General Test Classifications (5)

Assumptions

• Sampled using an appropriate sampling plan; Representative of the lot being tested

Packaging Material type Special Properties 

• Example: transparent, collapsible, easy to drain Integrity 

• Example: tightness, leak-free

Physical Properties

• Gross physical appearance 

  • Example: color, occurrence, odor, consistency, dimensions 

Potency Test

• determine conformance of dosage form to label claim

1. Instrumental Methods 

2. Chemical Methods 

3. Biological Methods

Methods Under Potency Test

Sampling

• comprises the operations designed to select a portion of a pharmaceutical product (for definition, see glossary) for a defined purpose. The sampling procedure should be appropriate to the purpose of sampling, to the type of controls intended to be applied to the samples and to the material to be sampled. The procedure should be described in writing

1. n plan

2. p plan

3. r plan

Sampling Plans and Techniques for Starting Material (3)

n plan

• when the material to be sampled is considered uniform and is supplied from a recognized source

• Samples can be withdrawn from any part of the container (usually from the top layer)

Formula of n plan

p plan

• when the material to be sampled is considered uniform and is supplied from a recognized source and the main purpose is to test for identity

Formula of p plan

r plan

• when the material is suspected to be nonuniform and/or is received from a source that is not well known

• used for herbal medicinal products used as starting materials.

Formula of r plan

Acceptable Quality Limit (AQL)

Sampling Plans and Techniques for Finished Products

AQL

• The quality level that is the worst tolerable over the course of many inspections

• used to determine how many units should be inspected and how many defects are acceptable during the inspection 

Statistical Quality Control

• the monitoring of quality by the application of statistical methods in all stages of production

1. Attribute Chart

2. Variable Chart

Two basic Quality Control Charts

Attribute Chart

• a chart when makes use of discrete data classifying the number of item conforming & the number of items failing to conform to any specified requirements 

•  Example: P chart and C chart

Variable Chart

• a chart using actual records of numerical measurement on a full continuous scale such as meter, grams, liter.

  • Example: X and R charts 

Formula of UCL

Formula of LCL

Formula of Center Line

1. Raw Materials Quality Control (RMQC)

2. In Process Quality Control

3. Finished Product Quality Control

3 Main Areas of Quality Control

1. Identity Test

2. Purity Test

3. Limit Test

4. Physical Test

5. Special Test

5 Tests Under RMQC

In Process Quality Control

• These are checks that are carried out before the manufacturing process is completed

• monitoring and if necessary, adaption of the manufacturing process to comply with the specifications 

1. Primary Moisture Content 31-35%

2. Adequacy of Wetness

3. Shape

4. Final Moisture Content : 0.5-1%

5. Angle of Repose

6. Porosity (Pores)

7. Bulk Density 

8. Tapped Density 

9. Carr’s Index

10. Hausner’s Ratio

11. Particle Size Distribution

12. Thickness

13. Hardness

Tests Under In Process Quality Control (13)

• Picking & Sticking

• Capping, Chipping, and Lamination

• High moisture: & ; Low moisture: , ,

Angle of Repose

• A constant 3D angle assumed by a cone-like pile of material

Porosity (Pores)

• measurement of the void or empty spaces of a material and is defined as the ratio between the volume of voids and the total volume

Bulk Density

• the density of a large volume of porous material powder including the pore spaces within the material particles in the measurement volume

Tapped Density 

• an increased bulk density attained after mechanically tapping a container containing the powder sample. The tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing the powder sample

Carr’s Index

• Index of compressibility

• Indication of the compressibility of a powder 

Hausner’s Ratio 

• measure of flowability 

Stroke Monsato

•  test of strength

1. Friability Test 

2. Hardness 

3. Thickness 

4. Disintegration Test 

5. Dissolution Test 

6. Uniformity of dosage units

6 Tests For Solid Dosage Forms

1. Bacterial Endotoxin Test 

2. Particulate Matter 

3. Pyrogen Test 

4. Clarity Test 

5. Safety Test 

6. Sterility Test 

7. Leaker’s Test

7 Tests For Parenterals

1. Microbial content 

2. Stability 

3. Sedimentation value

4. Redispersibility 

5. Rheological properties 

6. Electrophoretic Analysis 

7. Particle Size determination

7 Tests For Non-Sterile Products

1. Microbial content 

2. Spreadability 

3. Viscosity

3 Tests For Semi-solid

Stability

• Capacity of drug to remain within specifications 

• Established to assure identity, strength, quality, & purity

Acceptable Stability

• Time in storage and use in which a particular formulation in a container remains within physical, chemical, toxilogical, and bioavailability specifications.

Expiration Date

• Time in which the preparation will remain stable when stored under recommended conditions

• Too Early

• Too Late

• Type 1 Alpha Error :

• Type 2 Beta Error:

Harmful Events

• Decrease in therapeutic activity of preparation to below some arbitrary content 

• Appearance of toxic substances formed as degradation

Stability Studies

• Conducted within a span of 6 months

• 10 tabs

• 18 tabs

• 24 tabs

• 50 tabs

No. of samples 

• Appearance, Hardness, Thickness, Weight, Moisture = tabs 

• Disintegration = tabs

• Dissolution = tabs 

• Friability = tabs 

2 ½ years or 13 months

Ideal Shelf Life