British Pharmacopoeia for MPharm

Learning Objectives

  • Discuss the importance of quality control in medicine.
  • Explain the systems in place to ensure the quality of pharmaceutical products, especially the role of the British Pharmacopoeia (BP).
  • Describe the key sections in a typical drug monograph and explain how they are relevant in ensuring the quality of medicine.
  • Briefly discuss the challenges in quality control for modern medicines such as biologics.

Core Requirements for Medications

  • Safe: Does not kill patients.
  • Effective: Side effects are acceptable; demonstrates a pharmaceutical effect; demonstrates patient benefit.
  • Quality: Fits for the intended purpose.

Drug Concentration Profile

  • Key parameters in a drug concentration profile:

    • Onset: The time at which the drug starts to have an effect.
    • tmax: The time at which the drug reaches its maximum concentration.
    • Cmax: The maximum drug concentration achieved.
    • Duration: How long the drug's effect lasts.

  • Important concentration levels:

    • Minimum Effective Concentration (MEC): The minimum concentration required for the drug to be effective.
    • Minimum Toxic Concentration (MTC): The concentration above which toxic effects are likely to occur.

  • Therapeutic Index: A measure of the drug's safety, representing the range between the MEC and MTC.

Medicine Manufacturing Concerns

  • Ensuring the correct content and amount of the drug product.
  • Preventing contamination with harmful impurities.
  • Verifying that the drug dissolves according to the intended dissolution profile.

Role of the Pharmacist

  • Pharmacists are concerned with the nature of drugs and medicines, and their use.
  • The profession is split into two groups:
    • Scientists responsible for developing and formulating drugs as medicines.
    • Professionals involved in dispensing, legal regulation of medicines, and providing clinical advice.

Current Challenges in the Pharmaceutical Industry

  • Viable Business: The need to make a profit.
  • Globalization: Outsourcing of drug discovery, development, and manufacturing to smaller companies.
  • Adulteration: Deliberate debasing of medicines by adding other substances.
  • Counterfeiting: Illegal copies and worthless imitations intended to deceive.
  • Contamination: Pollution or infection of a product.

Globalization

  • Driving force behind the control of medicines.
  • Large pharmaceutical companies outsource discovery, development, and manufacturing.
  • Emergence of pharmaceutical companies in various regions.
  • Increased use of alternative medicines and increased international travel contribute to globalization's impact.

Adulteration

  • Deliberate debasing by adding other substances.
  • Common in food and drugs to increase profit.
  • Examples:
    • Street drugs cut with lactose.
    • Addition of lead or weeds to herbs to increase weight.
    • Adding coloring to medicine or herbs to create a fake appearance.

Counterfeit

  • Illegal copies and worthless imitations.
  • Intent to deceive consumers.

Contamination

  • Pollution or infection of a product.
  • Can be chemical or biological.
  • Caused by poor manufacturing equipment, storage conditions, and raw materials.

Protecting Public Health

  • Legally enforceable compliance with a regulatory body license.
  • Pharmacopoeias are needed (e.g., European, British, United States, Japanese, International).
  • In the UK, the focus is on the British Pharmacopoeia (BP).

Key Requirements for Medicine Licensing

  • Drugs/medicines must comply with requirements for:
    • Safety
    • Efficacy
    • Quality

Focus of a Pharmacopoeia Drug Monograph

  • Identity (content)
  • Purity (acceptable impurity levels)
  • Quantity (amount of drug)
  • Activity (to ensure safety, efficacy, and quality)

The British Pharmacopoeia (BP)

  • Produced by the British Pharmacopoeia Commission, part of the Medicines and Healthcare Products Regulatory Agency (MHRA).
  • Long history, dating back to 1864.
  • Used in over 100 countries.
  • Incorporates all text from the European Pharmacopoeia.

Key Features of the British Pharmacopoeia

  • Published annually.
  • Assists the licensing and inspection form the MHRA.
  • Comprehensive and advanced.
  • Provides the minimum requirements and standards for pharmaceutical products.

Comprehensive Nature of the British Pharmacopoeia

  • Complete set of 6 volumes.
  • Provides drug profiles and compliance procedures.
  • Includes descriptions of techniques employed.
  • Offers information about all materials used in laboratory procedures.

Monograph Focus

  • Pharmacopoeias mainly focus on the drug itself.
  • Excipients often remain food-like materials.
  • Compliance with all tests is mandatory.
  • No single test is sufficient.
  • Tests require simple equipment.

Monograph Headings

  • I. Definition
  • II. Character
  • III. Identification
    • Main issue: Confirm identity of the product.
    • No sophisticated technology is required.
    • Ultra-pure reference standards can be obtained from the Pharmacopoeia commission.
    • Typically, a series of 4-5 procedures is described, mainly chemical, although IR is prominent.
    • 2-3 procedures usually suffice to confirm the identity of the sample.

Purity Definition

  • Perfect purity would be 100% for a pure active ingredient.
  • Each case has its own limits, for example:
    • Pure Aspirin powder: 99.5% to 101%
    • Pure Paracetamol powder: 99% to 101%
    • Aspirin tablet: 95-105%
    • Paracetamol tablet: 95 to 105%
  • Solubility should be considered (refer to General Notices).

Identification Procedures

  • First Identification: A, B or B, C, D
    • A: IR (Infrared Spectroscopy)
      • Fewer procedures are usually needed with IR.
    • B: Chemical Tests
      • Boil in NaOH for 3 min (hydrolyze to salicylic acid).
      • Add sulfuric acid to give precipitate with a melting point at 156 °C - 161 °C.
    • C and D: Color tests

Tests (For Impurities)

  • Important for generics.
  • The impurity profile can demonstrate that a product has not been manufactured by a licensed route.
  • Impurities related to the drug are often called Related Substances.
  • Often uses separation analytical techniques for a detection limit and specificity that fit for purpose.

Possible Sources of Impurities

  • (a) Chemical
    • i) Production/manufacture
    • ii) Storage/stability
    • iii) Residual solvents
    • iv) Metals and ions.
  • (b) Particulates
    • “Insolubles” are often inorganic. This is the basis for the tests:
      • i) Turbidity (clarity/appearance)
      • ii) Sulphated ash
  • (c) Microbial/Bacterial endotoxin contamination

Limits and Quantification

  • Exact quantification requires reference to high accuracy and precision.
  • The BP prefers to refer to limits that should not be exceeded or within which a particular value should fall.
  • Each profile indicates the acceptable “limits” for compliance.
  • The expression of content is normally expressed as a “per cent”.
  • Levels of impurity need to be below an acceptable level (limit).

Impurities Limits Example

  • Stability:
    • Major impurities must be \le 0.1 \%
    • Sum of impurities must be \le 0.25 \%
  • Monitored by HPLC (High-Performance Liquid Chromatography) with a C8-column, mobile phase phosphoric acid/acetonitrile and A(237nm) detection.

Assay

  • How much of the sample is in fact the drug being dealt with, which applies to:
    • Pure drug
    • Formulated substance (e.g., tablet)
  • Methods used are:
    • Weightings
    • Titrations
    • Spectroscopy (specific absorbance)
    • Chromatography (comparing to an internal reference standard)

Assay Methods: Titrations

  • Titrations are a ubiquitous feature of the Pharmacopoeia for quantification from Acid/Base, to Potentiometer to non-Aqueous.
  • Complete numerical expectations are given in the monographs
  • Example: Aspirin assay involves adding Aspirin to an excess of NaOH, with the resulting excess of NaOH titrated with HCl.

Pharmacopoeia Monographs

  • Standardized analysis and quality control.
  • Method description and standardisation for chemical analysis, chromatography, and spectroscopy.
  • Includes products (medicines) as well as active ingredients (drugs).

Special Methods in Pharmacopoeia

  • Microbiology: Testing, purity, and potency evaluation.
  • Biologics: Protein drugs.

Sub-division of Therapeutics

  • Range of Pharmaceutical products: Active ingredients & Excipients.
  • A protein/peptide or a nucleic acid with up to ~200 residues should be capable of being fully characterised as a chemical entity.
  • Variations will arise due to:
    1. Heterogeneity – internal and external impurities
    2. Designed sequence variation
    3. Species sequence variation
    4. Glycosylation variation
  • Challenges: Antibodies, DNA plasmids, Chitosan.

Herbals Monographs

  • More descriptive, including:
    • Colour
    • Size and shape
    • Strength of the material when grinded
    • Appearance of cellular structure and morphology under a microscope
  • Traditional tests may be applicable:
    • Testing for the presence of active compounds
    • Weight loss upon drying

Biologics Monographs

  • Biologics are very complex and do not have "simple" monographs.
  • Some smaller Biologicals such as Insulin are now well-characterized and have a full chemical monograph, which may eliminate the need for a biological activity assay to ensure quality.

Summary

  • Distinguishing feature of the pharmacist as a member of the healthcare team.
  • Overview of techniques and their use.