EVALUATION OF QUALITY OF A DRUG PRODUCT

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EVALUATION OF QUALITY OF A DRUG PRODUCT

• Prepared and presented by
• Bekele Tefera
• EDM/NPO
• WHO country office-Ethiopia
• Work shop on Good Manufacturing Practice (GMP)
  good Distribution Practices (GDP) for domestic
  manufacturers, drug distributors and dug
  inspectors
• Nazareth, Ethiopia, 3-7 June 2002

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Summary

• One of the criteria for the scientific assessment
  of a drug product is quality.
• Application for registration of a new product
  must be accompanied by the following quality
  assurance data
• Development pharmaceutics
• Qualitative quantitative composition of the
  dosage form (including excepients)
• Method of manufacture of the dosage form
• Specifications of all the ingredients and the
  finished dosage form
• Analytical methods
• Stability data (stability study results)

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The above quality assurance data serve as a
basis for evaluation of the quality of a drug
product.

• Laboratory analysis / quality control is the cap
  stone for the evaluation of a drug product for
  registration.
• Some of the above quality assurance data will be
  discussed in detail below.

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Development Pharmaceutics

• Related to the different stages of new drug
  development
• Can be grouped in to two
• Pre formulation
• Formulation
• Pre formulation A phase of a research and
  development process where the pre formulation
  scientist characterizes the physical, chemical
  and mechanical properties of a new drug substance
  in order to develop stable, safe and effective
  dosage forms.

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Formulation

• the composition of a dosage form, including the
  characteristics of its row materials and
  operations required to process it.

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Stages of new drug

• development

Research concept discovery of lead compound
Pre clinical testing
Clinical testing
Registration with DRA
Launch Sale
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Pharmacy and chemical development works at each
research phase

• I Research concept and discovery of active lead
  compound
• (Involves 8,000-10,000 potential candidate
  substances)
• Focuses mainly on extraction/synthesis of active
  substances at laboratory scale
• II Preclinical testing
• 1 Selection of product candidate (basic
  pharmacology/biochemical screening) (20-30
  substances reach this stage)
• Analytical characterization of active substances
  is the main task

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2 Biological testing (pharmacological/toxicolog
ical studies)

• (5-10 substances reach this stage)
• Development of specific analytical methods of
  active substances, their degradation products and
  possible contaminants
• Pre formulation studies to determine formulation
  constraints and possibilities
• Synthesis of active substances at technical scale
• Consideration of alternative routes of synthesis
  of active substances

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Preparation of model formulation for clinical and
toxicological evaluation

• Synthesis of radio labeled compound for
  pharmacokinetic studies
• Development of analytical methodology
• Stability testing of active substances and model
  formulation
• Production of formulation of active substances
  and comparison formulation for clinical trials

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III Clinical trials ( phase I-II
)(Approximately 4-5 substances remain)

• Scale up of synthesis to pilot plant
• Development of analytical methods for Q.C testing
• Development of variety of formulations e.g.
  tablet, capsules, injections, etc
• Development of process of manufacture of
  formulation
• Design of chemical manufacturing plant
• Design of process of secondary pharmaceutical
  manufacture
• Confirmation of stability of products in the
  final packs
• Validation and finalization of Q.C methodology
  and specifications

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IV Registration with health authorities (1
substance remain )

• Design and preparation of packaging materials
• Construction/commissioning of chemical plant at
  full scale
• Validation of manufacturing process
• Development of quality assurance , in-process
  control procedures
• Construction and commissioning of secondary
  manufacturing units

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V Launch and sales

• Scheduling , ordering
• Production of final dosage form, packaging and
  product literature
• Quality control for release of products

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OTHER QUALTY ASSURANCE DATA

• Specifications
• Describe in detail the requirements with which
  products or materials used or obtained during
  manufacturing have to conform. They serve as yard
  sticks for quality evaluation
• Sources of specifications
• Pharmacopeal
• In-house

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Types of specifications

• Raw material specifications
• Container closure specifications
• Finished product specifications
• Finished product specifications
• Release specifications
• Stability indicating specifications

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Release specifications

• The combinations of physical, chemical,
  biological and microbiological test requirements
  that determine whether a drug product is suitable
  for release at the time of manufacture.
• Stability indicating specifications
• The combination of physical, chemical, biological
  and microbiological test requirements that the
  active ingredients or a drug product must meet
  during its shelf life

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EXAMPLES OF SPECIFICATIONS

• Active pharmaceutical ingredients
• Identity
• Purity
• Content
• Physico chemical properties such as solubility,
  melting points, particle size, etc.
• PH

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Finished product specifications

• General
• Organoleptic properties (appearance, color, odor)
• Identification
• Purity
• PH
• Moisture content
• Abnormal toxicity

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Specific

• Tablet dissolution/disintegration, weight
  variation, uniformity of content, friability,
  hardness, etc
• Capsules dissolution/disintegration, weight
  variation, brittleness, etc
• Injectables- Clarity, PH, sterility, pyrogen
  test (LVP), Volume, etc.
• Ophthalmic products- PH, sterility, weight
  variation, etc

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Analytical procedure (test method)

• Refers to ways of performing the analysis. It
  should describe in detail the steps necessary to
  perform each analytical test. This may include
  but not limited to the sample, the reference
  standard, the reagent preparation, use of the
  apparatus, generation of calibration curve, use
  of the formula for calculation, etc.

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The analytical method must be validated in terms
of

• Accuracy
• Precision (Repeatability, intermediate precision,
  reproducibility)
• Specificity
• Sensitivity (limit of detection, limit of
  quantification)
• Linearity
• Range
• Robustness

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REFERENCES

• Commission of the European community (1989) The
  rules governing medicinal products in the
  European community Guide to Good manufacturing
  Practice of medicinal products office for
  official publications of the European
  communities
• Gennaro A.R (1995) Remington's pharmaceutical
  science, 19th edition Mack publishing Co. , USA
• Gilman, AG (1990) The pharmacological basis of
  therapeutics, 8th edition. Macmillan publishing
  Co., USA
• ICH (1994) Harmonized Tripartite guideline-Text
  on validation of analytical procedures
  recommendation for adoption at step 4 of the ICH
  process on 27 October 1994 by the steering
  committee
• The British Pharmacopeal Commission (2000)
  British Pharmacopoeia

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The united states Pharmacopea commission(2000)
The united States Pharmacopea (USP 24) and
National Formulary (NF 19)

• US FDA (1990) From test tube to patient New
  drug development in the United States. USA
  Department of Health and Human Services. An FDA
  consumer special report. DHS publication No.
  90-3168
• WHO(1999) Marketing authorization of
  pharmaceutical products with special reference
  to multi source (generic) products,
  WHO/DMP/PRGS/98.5