Microbiology GMP PDF

# CGMP - Current Good Manufacturing Practices ## Chapter 06 ### CGMP Regulations - CGMP regulations were established by food and Drug Administration (FDA). - To ensure the premium standards for dry product quality. - **CGMP for Finished Pharmaceuticals:** #### Definitions: 1. **Organization &...

# CGMP - Current Good Manufacturing Practices ## Chapter 06 ### CGMP Regulations - CGMP regulations were established by food and Drug Administration (FDA). - To ensure the premium standards for dry product quality. - **CGMP for Finished Pharmaceuticals:** #### Definitions: 1. **Organization & Personnels** 2. **Building and Facilities** 3. **Equipment** 4. **Production & Process Control** 5. **Packaging and Labeling Control** 6. **Expiration Dating** 7. **Laboratory Controls** 8. **Records & Reports** #### Definitions: 1. **Active Pharmaceutical Ingredient:** Any ingredient that is intended to furnish pharmacological activity or other direct effects in the diagnosis, mitigation, prevention, or cure of a disease. 2. **Component:** Any ingredient used in the manufacturing of a drug product. 3. **Drug Product:** A finished form that contains an active drug and the inactive ingredients. 4. **Quality Control:** The regulatory process through which the industry measures quality performance and compares it with standards. 5. **Quality Control Unit:** A department in the industry made to ensure the quality of drug formed. 6. **Quarantine Area:** Area specified for the ingredients to be placed/stored before acceptance, testing, or qualification for use. ### Organization & Personnels - The organization of personnel section deals with the responsibilities of quality control unit, employees, and the consultants. - The quality control unit have the authority to accept or reject the drug formed, packaging, and labeling of a drug that may affect the product quality. - All personnels working in the industry are designated to them - packaging or holding of drug, supervisory positions, and education, training, and experience to fulfill the assigned duty. ### Buildings & Facilities - Regulations in this section include the design, structural features, functional aspects of building and facilities. - The place for drug manufacturing must be cleaned. - Some other factors such as water quality standards, security, materials used for ceiling, floors, walls, and lighting should be kept in consideration. - Control of heat, humidity, products storage, waste handling, sections must be present in the building. ### Equipment - Each piece of equipment must be of appropriate size and appropriate position to facilitate the operation for its intended use. - Standard operating procedures must be written and followed for the proper use, maintenance, and cleaning for each equipment. - Automated equipments must be validated and calibrated daily for accuracy. ### Production & Process Control - Written procedures are required for production and process control to ensure that the drug product have the correct identity, strength, quality, and purity. - Any deviation from the written procedures must be recorded and justified. - When operations are controlled by automated equipment, such equipment must be validated and calibrated regularly for precision. ### Packaging & Labeling Control - Written procedures are required for receipts, identification, packaging, and labeling of the drug product. - Labeling for each variation in drug strength, dosage form, or quantity of contents must be stored separately with suitable identification. - Access to the storage area must be limited to authorized personnels only. - All materials must be withheld for use in the labeling and packaging of product until approved and released by quality control unit. - Quantities issued, returned and used must be reconciled and investigated. - Each label must meet the requirement for the drug product and must have the product batch no. and product manufacturing and expiration date. ### Expiration Dating - To ensure that a drug product meet applicable standards of purity, strength, quality at the time of use, it must have an expiration date. ### Laboratory Controls - Laboratory controls are the requirements for establishment of written specifications, standards, sampling plans, test procedure, and other mechanisms. - The specifications which apply to each batch of dry product includes provision for sample size, test intervals, sample storage, stability testing, special testing requirements for certain dosage forms including parenterals, opthalmic, controlled-release products. ### Records & Reports - Production, control, and distribution records must be maintained for at least a year. - This includes equipment cleaning and maintaining logs, raw materials and products containers and closures and label records. - Complete master production and control record for each batch must be kept and must include: * Name and strength of product * Dosage Form * Quantitative amounts of components * Complete manufacturing and control procedures * Specifications. * Equipment used * Calibration of instruments ### Manufacturing of Sterile Products #### Sterilization - The process of killing or removing bacteria, all other forms of living organism, and their spores from the preparations. #### Methods of Sterilization Methods of sterilization have been divided into three categories: 1. **Physical Method:** * Dry heat sterilization * Sterilization by radiation * Moist heat sterilization 2. **Chemical Method:** * Gaseous sterilization * Sterilization by disinfectants 3. **Mechanical Method:** * Filtration ### Physical Method - Heat is the most effective and common means through which organisms are killed. - All the laboratory wears, glasswares, and hospital sugical instruments are made aseptic by heat in an autoclave. #### Dry Heat Sterilization - Dry heat is used to sterilize items but it requires much time to penetrate in the organism, so both the time and temperature should be increased to kill microorganisms fastly. - The standard time for hot oven is two hours at 160°C #### Substances Sterilized - Substances that are sterilized by heat are liquid parrafins, fixed oils, petroleum, propylene glycol, and powder. #### Mechanism - During dry heat sterilization, the bacteria and spores are killed through oxidation. As dry heat is less effective than moist heat, so higher temp. and longer period of time is required. #### Advantages: - Suitable for substances destroyed by moisture - Glass wares like flask, test tubes, pipettes can be sterilized. - Less damage to glass and metal equipments. #### Disadvantages: - Can't be used for volatile and thermolabile substances - Requires long heating time and high temp. - Not suitable for surgical dressings. #### Methods for Dry Sterilization 1. **Flaming:** - It is the simplest method of dry sterilization in which the material to be sterilized is kept in the hot part of the bunsen burner flame for few seconds and the process is repeated several times. - Eg: forceps, blades, knives sterilized. 2. **Hot Air Oven:** - It consists of metallic chamber of aluminum or stainless steel which is electrically heated and thermostat controlled. - Hot air oven is of two types: * In which air is circulated by gravity to all parts. * In which air is circulated by fan. * The later type is more satisfactory because sterilizing temperature is controlled. * Eg: Glass wares, comical flask, test tubes, pipettes etc. sterilized 3. **Incineration:** - Incineration will also burn the microorganisms to ash. - It is used to sanitize the medical and other biohazardous waste before it is discarded. ### Moist Heat Sterilization - It is the most reliable method of sterilization because in the presence of moisture, bacteria are destroyed at relatively low temperature rather than dry heating. #### Mechanism: - By this method, M-O are destroyed by denaturation and coagulation of some proteins present in the M.O. #### Advantages: - Microbes are killed more effectively. - Bulk quantities, surgical dressings and surgical instruments are effectively sterilized. #### Disadvantages: - Thermolabile substances and ointments can't be sterilized. #### Methods for Moist Sterilization 1. **Autoclaving:** - Autoclaving is the process of heating in an autoclave in which saturated steam under pressure is allowed to penetrate through the material for 20 mins at 121°C temp. #### Working - Usually uses heat steam at 121°C – 134°C. - To achieve sterility, holding time of at least 15-20 mins of 121°C and 3 min at 134°C. - Additional sterilization time is required for liquids and instruments, packed in layers of cloth. - After sterilization, autoclave liquids must be cooled slowly in order to avoid boiling over. - Proper sterilization will inactivate all fungi, bacteria, and virus. 2. **Heating with Bactericide:** - In this method, bactericide is added to the suspension or solution to be sterilized. - The sealed containers are then heated at 100°C for 30 mins in water bath. - This method is based on the fact that killing is done by heating as well as with bactericide. 3. **Sterilization by Boiling Water:** - The boiling water bath is most useful for sterilizing instruments like syringes, knives, blades, and scissors etc. 4. **Tyndalization:** - The method named after John Tyndal, which is useful for the killing of leftover bacterias after treating with boiling water. - The method involves heating for 20 mins, incubating for a day, boiling, incubating for a day, boiling, incubating for a day, and finally boiling again. - This three incubating periods allow to kill the left over M-O remained after previous boiling. ### Sterilization by Radiation - Sterilization by radiation is also known as cold sterilization because no heat is used in this method. #### Mechanism - By alternation irradiations, Chemicals takes place present in microorganisms, with the formation of new compound that kills the microbes. #### Advantages: - Used in the preservation of food and parenterals containing antibodies. - For the sterilization of some bacterial and viral vaccines. - No aseptic handling is required. #### Disadvantages - High cost. - Radiations are harmful to the person operating. - Radiations lead to change in colour, texture, and solubility. - Can lead to change in colour, texture, and solubility #### Methods of Sterilization by Radiation - **X-Rays:** X-rays are less penetrating than gamma-rays and tend to require longer exposure time. - Generated by X-ray machine. - Can be turned off when not in use. - **Gamma-Rays:** Gamma-rays are very penetrating and are commonly used for sterilization of disposable medical equipments such as syringes, needles, etc. - These rays require bulky shielding for safety of operator. - Also require storage of radioisotope that continuously emits gamma-rays. - **UV Light:** UV irradiations (UV from germicidal lamp) is most useful for sterilization of surfaces and transparent objects. - Many objects that are transparent absorbs most of the UV light. - UV light is routinely used to sterilize the interior of biological safety cabinets between uses. - It is ineffective in shaded areas or under dirt. - **Electron Beam Processing:** - It is also used for medical device sterilization. - Uses an on-off technology. - Dosing rate is higher than X-rays and Gamma rays. - Less exposure time is required because of high dosing rate. ### Chemical Sterilization - Chemicals are also used for sterilization. - Although heating provides the most reliable way to get rid of all types of M-O, but it is not always appropriate. Because it can damage heat sensitive instruments like fiber optics, electronics & plastics. #### Chemical Sterilization Includes: - Ethylene oxide - Formaldehyde - Ozone - Hydrogen peroxide, prions - Chlorine bleach #### Ethylene Oxide - ETO is commonly used to sterilize objects sensitive to temp. greater than 60°C. - It is carried out at 30°C – 60°C, with humidity above 30%, gas conc. between 200-800mg/L, for at least three hours. - ETO penetrates well through paper, cloth, and plastic. - Used to sterilize sensitive instruments. - All virus, bacteria and other M-O are killed by ETO. - It is highly flammable. - Requires a longer time to sterilize than heat. ### Preservatives - Preservatives are the static agents used to inhibit the growth of microorganisms, most often in foods. - If eaten, they should be non-toxic. ### Anti-Microbial Agents - Anti-microbial agents are chemicals that kill or inhibit the growth of M-O. - Antimicrobial agents include chemical preservatives and antiseptics, as well as drugs used in the treatment of infectious diseases of plants and animals ### Types of Anti-Microbial Agents - **Antiseptics:** Microbicidal agents harmless enough to be applied to the skin and mucous membrane, should not be taken internally. - **Disinfectants:** Agents that kill microorganisms but not necessarily their spores, but are not safe for application to living tissues. - They are used on inanimate objects such as tables, floors etc. ### Control of Microbial Contamination - To control the microbial contamination, following steps should be taken: 1. **Risk Assessment by Hazard Analysis of Critical Control Points (HACCP):** * It is a tool for evaluating steps in manufacturing process which involves following steps: * Analysis and identification of potential hazard or risk of each step. * Determine the critical points. * Establishing the critical limits. * Establishing the system to monitor the critical control point. * Establish the corrective measures to be taken. 2. **Environmental Cleanliness and Hygiene:** * Microorganisms may be transferred to a product from working surfaces, fixtures, and equipments. * Thus it is essential that all the premises including processing areas, stores and laboratories should be maintained in a clean and tidy condition. * All the ceilings, walls and floors should be easily washable. * Floors should be free from cracks where microorganisms can easily grow. * All equipments used in the manufacturing process should be easy to clean and dismantle. * Personnel are other source of contamination. Therefore high standards of personal hygiene are essential. * To ensure personal hygiene, hand disinfection facilities, adequate hand washing and protective garments including headgear, gloves should be provided. 3. **Quality of Starting Materials:** * Raw materials account for a high proportion of the microorganisms introduced during the manufacture of pharmaceuticals. * The selection of materials of good quality helps in the control of contamination level. * It is necessary to store properly the raw material to prevent the growth of organisms and spoilage of material. * If stable, some natural products with high microbial count may undergo sterilization before use. 4. **Water:** * Most type of water are derived from municipal supplies. * Such water is treated by filtration and always by chemicals specifically chlorine to make it free from microorganisms. * Microbial count in water varies from region to region and can increase on storage. 5. **Process Design:** * The manufacturing process must be fully defined and capable of yielding with the facilities available, a product that is microbiologically acceptable and conforms to its specifications. * The process must be validated fully before starting to ensure that is suitable for routine production operations. 6. **Quality control and documentations:** * The lower the microbiological count of the startry material, the more readily the quality of the product can be controlled. * Microbiological quality assurance also covers the validation of cleaning and disinfectant solutions and the monitoring of the environment should be carried out while normal production operations are in progress. 7. **Packaging, Storage & Transport:** * Packaging serves a number of functions. * It keeps the contaminants out. * The product is then ined in primary package and is conta ined inside secondary packages. * Consideration must be given to the fabric of package and its cleaning, and the actual process of packaging. * Packaging material has a dual sole and acts both to contain the product and to prevent the entry of M-O or moisture which may result in spoilage.