The manufacturing process of bio-drugs

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The manufacturing process of bio-drugs

• The manufacture of biopharmaceutical substances
  
• - Most highly regulated and rigorously
  controlled processes
• To gain a manufacturing license, the producer
  should prove that not
• only the product itself is safe and effective,
  but all aspects of the
• proposed manufacturing process comply with the
  highest quality
• standards
• The bio-drugs approved for medical use should be
  produced using the same process by which it is
  intended to undertake pre-clinical and clinical
  trials
• ? Best manufacturing process (Bioprocess)
  should be established

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• The factors affecting the safe manufacture of
  quality bio-drugs
• - Design and layout of the manufacturing
  facility
• - Raw materials utilized in the manufacturing
  process
• - Manufacturing process itself
• - Training and commitment of personnel
  involved
• in all aspects of the manufacturing
  operation
• - Existence of a regulatory framework which
  assures the
• establishment and maintenance of the highest
  quality
• standards regarding all aspects of
  manufacturing

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Overview of manufacturing process

• Key elements
• - Clean room, Equipment, Personnel, Water,
• Documentation (Product standards, protocols,
  guidelines)
• Infrastructure of a typical manufacturing
  facility and some relevant operational issues
• Source of biopharmaceuticals
• Up-stream and down-stream processing of
  biopharmaceutical products
• Analysis of the final products Quality control

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International Pharmacopoeia

• Most important factors that determine the safety
  and efficacy
• - Standard of raw materials used in the
  manufacturing process
• - Standard (specification) to which the final
  product is produced
• Standard processes and guides to good
  manufacturing practice for medicinal products
  Play a central role in establishing criteria
  which guarantee the consistent production of safe
  and effective bio-drugs
• Most pharmaceutical substances are manufactured
  to exacting specifications in publications
  Pharmacopoeias
• - International Pharmacopoeias
• - US (USP), European Pharma ( Eur. Ph.),
  Japanese Pharmacopoeia
• - Products listed in pharmacopoeias generic
  drugs

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Martindale

• The extra pharmacopoeia
• To provide concise, unbiased information
  regarding bio-drugs of clinical interest, largely
  summarized from the peer-reviewed literatures
  not a book of standards
• First edition published by William Martindale in
  1883
• - The 30th edition in 1993
• Contains information on around 5,000 bio-drugs in
  clinical use Chemical-based drugs and
  traditional biological substances like
  antibiotics, hormones, and blood products

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• Classified based on similar clinical uses or
  actions
• Information about
• - Physio-chemical characteristics
• - Absorption and fate
• - Uses and appropriate mode of administration
• - Adverse/side effects
• - Suitable dosage levels
• List of the major headings under which various
  drugs are described in Martindale Table 3.1

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Guides to Good Manufacturing Practice

• All aspects of biopharmaceutical manufacture must
  comply with the most rigorous standards to ensure
  consistent production of a safe and effective
  bio-drugs
• Principles underlining such standards are
  summarized in publications which detail Good
  Manufacturing Practice (GMP)
• - EU guide to Good Manufacturing Practice for
  
• Medicinal Products

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• Biopharmaceutical manufacturers must be familiar
  with the principles, and are legally obliged to
  ensure adoption of these principles to their
  specific manufacturing process
• Regulatory authority assesses compliance of the
  manufacturer with the principles by undertaking
  regular inspections of the facility
• Subsequent granting/renewing (or refusing) of a
  manufacturing license depends largely on the
  level of compliance found during the inspection

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Principles outlined in GMP

• Each chapter is concerned with a specific aspect
  of pharmaceutical manufacture Common-sense
  guidelines
• - List of contents in the EU Guide to GMP for
  Medicinal
• products Table 3.2
• GMP in relation to personnel
• - Adequate number of sufficiently qualified,
  experienced personnel
• should be employed by the manufacturer
• - Key personnel, such as the heads of
  production and quality control,
• must be independent of each other
• - Personnel should have well-defined job
  descriptions, and should
• receive adequate training
• - Issues of personal hygiene should be
  emphasized to prevent
• product contamination

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Principles regarding Premises and equipments

• All premises and equipment should be designed,
  operated, and serviced to carry out their
  intended functions
• Facility and equipment should be designed and
  used to avoid cross-contamination or mix-up
  between different products
• Sufficient storage area must be provided, and
  clear demarcation must exist between storage
  zones for materials at different levels of
  processing (raw materials, partially processes
  products, finished products etc..)

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• Quality control labs must be separated from
  production, and must be designed to fulfill their
  intended function
• Some of the principles outlined in the guide are
  sufficiently general to render them applicable to
  most manufacturing industries
• Most of principles outlined in guides to GMP are
  equally as applicable to the manufacture of
  traditional pharmaceuticals as to new ones
• Many of the guidelines are specific Guidelines
  relating to the requirement for dedicated
  facilities when manufacturing specific products

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Manufacturing facility

• Appropriate design and layout of the facility
  Crucial to the production of safe and effective
  medicines
• Commonly contains
• - Specific production of a target drug
• - Quality control, Storage areas, etc
• cf) Injectable bio-drugs Require unique
  facility design and operation ? safety of product
  
• - Clean room technology
• - Generation of ultra pure water (WFI
  water for injection)
• - Proper design and maintenance of
  non-critical
• areas storage, labeling, and packing
  areas

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Clean rooms

• Environmentally controlled areas for
  injectable/sterile biopharmaceutricals
  specifically designed to protect the product from
  contamination (microorganisms and particulate
  matters etc.)
• Designed in a way that allows tight control of
  entry of all substances and personnel (e.g.,
  equipment, in-process product, air etc..)
• A basic feature of design Installation of high
  efficiency particulate air (HEPA) filters in the
  ceilings

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• - Layers of high-density glass fiber
  Depth filter
• - Flow pattern of HEPA-filtered air Fig.
  3.1
• - Air is pumped into the room via the
  filters,
• generating a constant downward
  sweeping motion
• Clean rooms with various levels of cleanliness
• - Classified based on the number of airborne
  particles
• and viable microorganisms in the room
• - Maximum permitted number of particles or
  microorganisms per m3 of clean room air

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• Europe
• 5 µm particle dia viable
  microorganisms
• Grade A 0
  lt 1
• B 0
  5
• C 2,000
  100
• D 20,000
  500
• USA
• class 100 (grade A/B),
• class 10,000(grade C),
• class 100,000 (grade D)

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Factors affecting the clean room condition

• Use of HEPA filters with high particulate-removing
  efficiency
• Generation of a unidirectional downward air
  distribution pattern (i.e. laminar flow)
• Additional elements critical to maintaining
  intended clean room conditions
• - All exposed surfaces a smooth, sealed
  impervious finish in order to minimize
  accumulation of dirt/microbial particles to
  facilitate effective cleaning procedures
• - Floors, walls, and ceilings coated with
  durable, chemical-resistance materials like epoxy
  resins, polyester, PVC coatings

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• - Fixtures (work benches, chairs, equipments
  etc..) designed and fabricated to facilitate
  cleaning processes
• - Air-lock systems buffer zone
• - prevention of contamination
• - entry of all substances/personnel into a
  clean room
• must occur via air-lock systems
• An interlocking system doors are never
  simultaneously open, precluding formation of a
  direct corridor between
• the uncontrolled area and clean area
• Generalized clean room design Figure 3.2
• - Separated entries and exits for personnel,
  raw materials,
• and products

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• Personnel represent a major potential source of
  process contaminants required to wear
  specialized protective clothing when working in
  clean area
• Operators enter the clean area via a separated
  air-lock
• High standard of personnel hygiene
• Only the minimum number of personnel required
  should be present in the clean area at any given
  time

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Cleaning, decontamination, and sanitation (CDS)

• CDS regime essential to the production of a
  safe and effective biopharmaceuticals
• - Cleaning removal of dirt
  (organic/inorganic materials)
• - Decontamination inactivation and removal
  of undesirable
• substances, which generally exhibit some
  specific biological activity
• ex) endotoxins, viruses, prions
• - Sanitation destruction and removal of
  viable microorganisms
• Effective CDS procedures are routinely applied to
  
• - Surfaces are not direct contact with the
  product (e.g. clean room
• walls and floors)
• - Surfaces coming into direct contact with
  the product (e.g.
• manufacturing vessels, product filters,
  columns)

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• CDS of process equipment
• - surfaces/equipment in direct contact with
  the product special
• CDS requirement
• - no trace of the CDS reagents ? product
  contamination
• ? Final stage of CDS procedures involves
  exhaustive rinsing with
• highly pure water (water for injections
  (WFI))
• CDS of processing and holding vessels as well as
  equipment that is easily detachable/dismantled
  (e.g., homogenizer, centrifuge rotors etc.,) ?
  straightforward

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• Cleaning in place(CIP) large equipment/process
  fixtures due to the impracticality/undesirability
  of their dismantling
• ex) internal surfaces of fermentation
  equipment, fixed piping, large
  processing/storage tanks, process-scale
  chromatographic column
• - General procedure A detergent solution in
  WFI, passage of sterilizing live steam generated
  from WFI
• CDS of process-scale chromatography systems
  challenging
• ex) Processing of product derived from
  microbial sources contamination with lipid,
  endotoxins, nucleic acids, proteins

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Water for biopharmaceutical processing

• Water One of the most important raw materials
  
• ? used as a basic ingredient
• - Cell culture media, buffers, solvent in
  extraction and
• purification, solvent in preparation of
  liquid form and
• freeze-dried products
• - used for ancillary processes cleaning
• - 30,000 liters of water production of 1
  kg of a
• recombinant biopharmaceutical produced in
  a
• microbial system
• ? Generation of water of suitable purity
  central to
• successful operation of facility

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• Two levels of water quality purified water and
  WFI
• - Outlined in international pharmacopoeias
• Use of purified water
• - Solvent in the manufacture of aqueous-based
  oral products (e.g., cough mixtures, )
• - Primary cleaning of some process
  equipment/clean room floors in class D or C area,
  
• - Generation of steam in the facilities,
  autoclaves
• - Cell culture media
• Water for injection (WFI)
• - Highest purity
• - Extensive use in biopharmaceutical
  manufacturing

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Generation of purified water and WFI

• Generated from potable water
• Potential impurities in potable water Table 3.7
• Multi-step purification steps for purified water
  and WFI
• Monitoring of each step continuous measurement
  of the resistivity of the water
• ex) Deionization anion/cation exchangers
• ?Increased resistivity with purity up to 1-
  10 MO
• Filters to remove microorganisms 0.22 µm, 0,45
  µm
• Reverse osmosis (RO) membrane Semi-permeable
  membrane (permeable to the solvent, water, but
  impermeable to solute, i.e., contaminants)

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General procedure for WFI

• Potable water
• ? depth filtration? organic trap (resin)
• ? activated charcoal
• ? Anion exchanger? Cation exchanger
• Deionization step monitored by measuring
  the
• water resistivity
• ? Filtration with membrane to remove
  microorganisms
• - purified water
• ? Distillation (or reverse osmosis)
• ? Water for injection(WFI)

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Documentation

• Adequate documentation Essential part of GMP
• Essential in order to
• - Help prevent errors/misunderstandings
  associated
• with verbal communication
• - Facilitate the tracing of the manufacturing
  history of
• any batch of product
• - Ensure reproducibility in all aspects of
  pharmaceutical
• manufacture

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Categories

• Most documents associated with biopharmaceutical
  manufacturing fall into one of four categories
• - Standard operating procedures (SOPs)
• - Specifications
• - Manufacturing formulae, processing and
• packaging instructions
• - Records
• Documents should be written/worded in a clear and
  unambiguous fashion by supervisory personnel and
  inspected by senior technical personnel like
  production or QC manager before final approval
  for general use

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SOPs (Standard Operating Procedures)

• Documents detailing how staff should undertake
  particular procedures or processes
• General categories
• - SOPs detailing step-by-step operational
  procedures for specific items of equipment (e.g.,
  autoclave, homogenizer, freeze-dryers etc.,)
• - SOPs detailing maintenance/validation
  procedures for specific items of equipment or
  facility areas, e.g., SOPs detailing CDS of clean
  rooms
• - SOPs relating directly to personnel (e.g.,
  step-by-step procedures before entering a clean
  room)
• - SOPs relating to testing/analysis (e.g., QC
  analysis of final product
• how to properly sample raw
  materials/products, testing of WFI etc.)

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Specifications

• Exact qualitative and quantitative requirements
  for raw materials or product
• - Specifications for raw material (ex.,
  percentage active
• ingredients, permitted levels of
  impurities)
• - Specifications for packing materials (ex.,
  exact dimension
• of product packaging, details of product
  labels etc.)
• - Specifications for final product (ex.,
  purity, color,
• formulation etc.)
• Normally written by QC personnel
• Specifications for raw materials / final product
  conforming with appropriate pharmacopoeia

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Manufacturing formulae, processing and packaging
instructions

• Provide sufficient information to allow a
  technically competent person to successfully
  undertake the manufacturing procedure
• Manufacturing formulae
• - Product name, potency / strength, exact
  batch size, starting raw materials, quantity of
  each material
• - Processing instructions
• Principal items of equipment, precise
  location where each step should be undertaken (e
  g., in a specific clean room), specific
  precautions during manufacturing, labeling of
  each product and packing instructions
• A copy of the label to be used is generally
  attached to the documents

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Records

• Maintenance of adequate and accurate records
• For any given batch of product, records relating
  to every aspect of manufacture are retained for
  at least 1 year
• Records include
• - Specification results obtained on all raw
  materials
• - Batch manufacturing, processing, and
  packaging records
• - QC analysis results of bulk and finished
  product
• The records should allow tracing back of all
  manufacturing steps, for the case of any
  difficulty or problem regarding the production of
  final product