2. The drug manufacturing process (1).pdf

GOOD MANUFACTURING PROCESSES Dr. Shatavari Kulshrestha  REGULATION AND CONTROL OF PHARMACEUTICAL MANUFACTURING PROCESS The regulatory authorities need to be proven that not only is the product itself safe and effective, but that all aspects of the proposed manufacturing pro...

GOOD MANUFACTURING PROCESSES Dr. Shatavari Kulshrestha  REGULATION AND CONTROL OF PHARMACEUTICAL MANUFACTURING PROCESS The regulatory authorities need to be proven that not only is the product itself safe and effective, but that all aspects of the proposed manufacturing process comply to the highest safety and quality standards Various elements contribute to the safe manufacture of quality pharmaceutical products o the design and layout of the manufacturing facility o raw materials utilized in the manufacturing process o the manufacturing process itself o the training and commitment of personnel involved in all aspects of the manufacturing operation o the existence of a regulatory framework for the establishment and maintenance of the highest quality standards with regard to all aspects of manufacturing  INTERNATIONAL PHARMACOPOEIA Most pharmaceutical substances are manufactured to exacting specifications laid down in publications termed ‘pharmacopoeias’ the United States Pharmacopoeia (USP) the European Pharmacopoeia (Eur. Ph.) the Japanese Pharmacopoeia Most of the drug listed in these pharmacopeia are invariably generic drugs The International Pharmacopoeia is a collection of recommended procedures for analysis and specifications for active pharmaceutical ingredients, excipients and finished pharmaceutical products (refer appendix 3 of Gary Wash (2011) Biopharmaceuticals: Biochemistry and biotechnology , second edition)  MARTINDALE, THE EXTRA PHARMACOPOEIA Additional publication of relevance to the pharmaceutical industry The aim of this encyclopedic publication is to provide concise, unbiased information (largely summarized from the peer reviewed literature) regarding drugs of clinical interest Martindale is largely organized into chapters that detail groups of drugs having similar clinical uses or action The information presented in a monograph detailing any particular drug will usually include: physiochemical characteristics absorption and fate uses and appropriate mode of administration adverse/side effects suitable dosage levels  GOOD MANUFACTURING PRACTICES o GMP are rigorous standards to ensure consistent production of a safe, effective product are summarized in form of publications o Pharmaceutical manufacturers are legally obliged to ensure adoption of these principles to their specific manufacturing process o Regulatory authority personnel will assess compliance of the manufacturer -regular inspections of the facility o Granting/renewing (or refusing/revoking) of a manufacturing license depends largely upon the level of compliance found during the inspection The European Union (EU) publishes the EU Guide to Good Manufacturing Practice for Medicinal Products This guide consists of a number of chapters, each of which is concerned with a specific aspect of pharmaceutical manufacture 1. Quality management 2. Personnel 3. Premises and equipment 4. Documentation 5. Production 6. Quality control 7. Contract manufacture and analysis 8. Complaints and product recall 9. Self-inspection The regulatory authorities have found it necessary to publish additional guidelines relating to many of the newer biotechnology-based biopharmaceuticals ‘Points to Consider’ series, which contain guidelines relating to safe production, e.g. of therapeutic monoclonal antibodies by hybridoma technology, and recombinant biopharmaceuticals produced by genetic engineering Reference: Gary Wash (2011) Biopharmaceuticals: Biochemistry and biotechnology , second edition Reference: Gary Wash (2011) Biopharmaceuticals: Biochemistry and biotechnology , second edition  MANUFACTURING FACILITY Cleanroom environmentally controlled areas within the pharmaceutical facility in which critical manufacturing steps for injectable (parenteral)/sterile (bio)pharmaceuticals must be undertaken Common potential contaminants include microorganisms and particulate matter These contaminants can be airborne, or derived from process equipment, personnel, etc designed in a manner that allows tight control of entry of all substances (e.g. equipment, personnel, in-process product, and even air High-efficiency particulate air (HEPA) filters Presence of HEPA filters in their ceilings These depth filters, often several inches thick, are generally manufactured from layers of high-density glass fiber Air is pumped into the room via the filters, generating a constant downward sweeping motion The air normally exits via exhaust units, generally located near ground level This motion promotes continued flushing from the room of any particulates generated during processing Reference: Gary Wash (2011) Biopharmaceuticals: Biochemistry and biotechnology , second edition Laminar flow is defined as airflow in which the entire body of air within a designated space is uniform in both velocity and direction HEPA filters of different particulate-removing efficiency are available, allowing the construction of clean rooms of various levels of cleanliness Such rooms are classified on the basis of the number of (a) airborne particles (b) viable microorganisms present in the room In Europe clean rooms are classified as grade A, B, C or D (in order of decreasing cleanliness) In the USA, cleanrooms are classified as class 100 (equivalent to grade A/B), class 10 000 (grade C) or class 100 000 (grade D) HEPA filters in grade B, C and D clean rooms are normally spaced evenly in the ceiling, occupying 20–25% of total ceiling area Generation of class A clean room conditions The use of high-specification HEPA filters, along with the generation of a unidirectional downward air distribution pattern (i.e. laminar flow), is essential This is only achieved if filter occupancy of ceiling space is 100% Most commonly, portable (horizontal or vertical) laminar flow cabinets placed in class B cleanrooms are used to generate localized class A conditions  CLEAN ROOM DESIGN All exposed surfaces should have a smooth, sealed impervious finish in order to minimize accumulation of dirt/microbial particles and to facilitate effective cleaning procedures Floors, walls and ceilings can be coated with durable, chemical /resistant materials, such as epoxy resins, polyester or PVC coatings Such surfaces may be completely overlaid with smooth vinyl-based sheets, thermally welded to ensure a smooth, unbroken surface  Fixtures within the room (e.g. work benches, chairs, equipment, etc.) should be kept to a minimum, and ideally be designed and fabricated from material that facilitates effective cleaning (e.g. polished stainless steel) The positioning of such fixtures should not hinder effective cleaning processes Pipework should be installed in such a way as to allow effective cleaning around them and the presence of uncleanable recesses must be avoided All corners and joints between walls and ceilings or floors are rounded, and equipment with movable parts (e.g. motors, pumps) should be encased  TRANSFER OF PROCESS MATERIAL AND ENTRY OF PERSONNEL The principles of GMP minimizes risks of contamination by stipulating that entry of all substances/personnel into a clean room must occur via air-lock systems Such air-locks, with separate doors opening into the clean room and the outside environment, act as a buffer zone All materials/process equipment entering the clean area are cleaned, sanitized, (or autoclaved if practicable) outside this area, and then passed directly into the transfer lock, from where it is transferred into the clean room by clean room personnel Generalized clean room design  Transfer locks are positioned between adjacent clean rooms of different grades of cleanliness Personnel represent a major potential source of process contaminants so they are required to wear specialized protective clothing when working in clean areas Operators enter the clean area via a separate air lock, which serves as a changing area. They remove their outer clothing at one end of the area, and put on (usually pre-sterilized) gowns, face masks and gloves at the other end of the changing area clean room clothing is made from non-shedding material, and covers most of the operator’s body Generalized clean room design  A high standard of operator personal hygiene is also of critical importance, and all personnel should receive appropriate training in this regard Only the minimum number of personnel required should be present in the clean area at any given time. This is facilitated by a high degree of process automation The installation in clean room walls of windows that serve as observational decks, coupled with intercom systems, also helps by facilitating a certain degree of supervision from outside the clean area