Pharmaceutical Manufacturing Overview

Manufacturing Activities

• Production involves all stages of drug product manufacturing
• Batch manufacturing records (BMRs) or master batch records (MBRs) document the process
• A batch is a specific quantity of drug product with uniform character and quality
• A lot is a portion of a batch
• Batch/lot numbers provide identification and traceability
• Warehouses store materials and finished products
• Incoming components are held in a quarantine area (yellow label)
• Purchasing and logistics are warehouse activities

Departments in a Manufacturing Company

• Research and development: formulates new products, improves existing products, and prepares the master formula (with overages)
• Overage: addition of excess API, in an unstable preparation

Quality Control

• Tests for compliance with material specifications
• Conducts sampling and testing
• Performs in-process quality control and environmental testing

Marketing

• Studies current trends, consumer behavior, and product status
• Advertisement and promotion activities

Regulatory

• Ensures compliance with pertinent laws and regulations
• Licensing to operate (LTO) and certificate of product registration (CPR) are required

Engineering

• Installs, maintains, and repairs equipment
• Conducts validation and qualification

Solid Dosage Forms

• Formulator Components
  • Diluents (fillers/bulking agents): inert substances increasing tablet size/filling capsule body
  • Other components:
    • Lactose: most common, anhydrous/spray dried
    • Sucrose and Dextrose: microcrystalline cellulose, starch
    • Multifunctional: Dibasic Calcium Phosphate, mannitol, xylitol
    • Starch paste, acacia, tragacanth, gelatin
    • Cellulose derivatives: methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose
    • Disintegrants: facilitate tablet breakup in an aqueous medium ("double disintegration")
      • Examples: sodium starch glycolate (Primojel/Explotab), crospovidone, croscarmellose Na
    • Anti-frictional agents: reduce friction and improve flow.
      • Example: hydrophobic agents added at low concentrations prior to compression
    • Lubricants: reduce friction
    • Glidants: reduce friction between particles to enhance flow
    • Antiadherents: prevent sticking
    • Colorants: dyes to disguise off-color drugs and improve appearance.
    • Examples: synthetic organic colorants, lakes (dyes adsorbed on an inorganic oxide; iron oxide, aluminum oxide)
    • Stearates (Mg, Ca, Na): lubricant, anti-adherent, glidant, and stearic acid
    • Purified Talc: anti-adherent, lubricant
    • Colloidal Talc, Colloidal SiO2 (cab-o-sil), silicates (Ca,Mg): glidants
• PEG & Lauryl Sulfate & Sodium Hydrophillic Lubricants

Flavorants

• Masks unpleasant tastes of drugs
• Examples: Salty (cinnamon, orange, cherry, butterscotch), Bitter (chocolate, cherry, raspberry), Sour (fruity), Oily (mint, orange, lemon), Unpleasantly sweet (vanilla and fruity)

Blending, Overshadowing, and Physical Properties

• Blending: combines fruit flavors with sour tastes, and bitter, salty, sweet, sour tastes to reduce sourness and increase sweetness
• Overshadowing: uses flavors whose intensities are stronger than the obvious flavor
• Physical Properties: formation of insoluble compounds, emulsification of oils, effervescence, high viscosity of fluids, coating of tablets.
• Chemical properties: adsorption of the drug on a substance, and formation of a complex of the drug

Unit Processes (Tablets)

• Dispensing: weighing and measuring materials
• Milling: particle size reduction, (e.g. crushing, grinding)
• Mixing: blending materials, achieving uniform mixing and removing color distribution issues (avoiding segregation)
• Batch Type Mixer: All materials are loaded together, mixed for a long period, and discharged in a single batch.
• Continuous Mixer: material continuously travels and moves through the equipment, mixing while traveling.
• Granulation: involves powder size enlargement into granules
• Dry Granulation: utilizes double compression to form large tablets, which are then crushed
• Tableting: compression of materials within the die cavity by the pressure exerted by the punches

Coating

• Double Impression: Due to free rotation of the punches
• Mottling: uneven color distribution
• Sweating: oily film due to humidity conditions
• Bridging: markings are obscured due to the coating pulling away within the logo
• Logo-infilling: due to coating accumulated in the logo areas
• Chipping: due to excessive moisture, causing adhesion of the material to the press punch, or lack of binder
• Crackling, sticking: due to excipients and expansion of the tablets
• Film Cracking: Due to thermal expansion of tablet cores during over-drying, or excessive moisture uptake
• Delayed Dissolution: exposure to coating process conditions

Capsules

• Hard Gelatin Capsules (HGC): manufacture in separate operation (filling)
• Soft Gelatin Capsules (SGS): formed, filled, and sealed in a single operation.

Semisolid Dosage Forms

• Ointments: incorporation of components, mix until uniform, may include fusion
• Gels: substances with high viscosity increase is added
• Other: homogenizers, ultrasonifiers, and chemicals (acids, esters, etc.)

Stability Enhancers

• Preservatives: prevent microbial growth
• Antioxidants: prevent oxidation of ingredients (APIs, fats, and oils)

Packaging and Storage

• Packaging for protection from pollutants and environment.
• Types: Primary Packaging (direct contact with the product) and Secondary Packaging (outer packaging)
• Classification: Well-closed, tight, hermetic, light-resistant, child-resistant, tamper-resistant
• Types of Containers -Bottles, Caps, Liners, Fillers, etc

Sterilization Methods

• Moist Heat: autoclaving (121 degrees, 15 psi, 15-20 minutes)
• Dry Heat: oven sterilization (160°C - 170°C, 2-4 hours)
• Filtration: using Membrane filters, 0.23 µm filters
• Gas: using ethylene oxide, formaldehyde, B-propiolactone
• Ionizing radiation: using Gamma or cathode rays

Clean Rooms

• Classification based on particle concentration (e.g., ISO Class 100, 1000, 10,000)
• Cleanroom procedures for handling, storage, and preparation of sterile products.
• Procedures for cleaning and sterilization of equipment in the preparation areas.

Types of Polymers

• Polyethylene, terephthalate, high-density polyethylene, polyvinyl chloride, low-density polyethylene, polypropylene
• Metal, Foil, Films and laminates, Rubber, Paper.