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Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on
MANUFACTURING PHARMACY
Manufacturing Pharmacy
● Deals with the technology of various official and non-official products manufactured in a semi-commercial and commercial scale. INDUSTRIAL PHARMACY ● Refers to the pharmaceutical research and manufacturing companies providing pharmacists with medicines in pre-fabricated or ready to take-form. OBJECTIVES IN THE MANUFACTURE OF DRUGS AND COSMETICS
- Familiarization of oneself to the facilities and functions of each in a pharmaceutical manufacturing pharmacy.
- To gain knowledge and awareness of the provisions of CGMP and apply these laws in the laboratory.
- To determine the protocols and the schematic flow of documents and steps in the manufacture of a pharmaceutical product.
- To know the different methods of stability testing AIMS OF DRUG FORMULATION ● Patient’s acceptance ● Compliance with physical and chemical specifications ● Stability ● Avoidance of batch-to-batch variation ● Maximum therapeutic effectiveness ● Freedom from unacceptable side effects DRUGS ● As any substance or mixture of substances manufactured for use in: ○ The diagnosis, treatment, mitigation or prevention of disease, abnormal physical state, or the symptoms thereof in man or animal. ○ Restoring, correcting, or modifying organic function in man or animal. IN INDUSTRY CIRCLES ● Drugs are called Pharmaceuticals ● It includes quasi-drugs as well as cosmetics, narcotics, food coloring, and preparations, infant milk, baby food, insecticides, herbicides, rodenticides, parasiticides, etc. CLASSIFICATION OF DRUGS I. According to Therapeutic Action a. Example: antibiotic, cough & cold remedies, vitamins, analgesic, antacid, etc. II. According to Method of Dispensing a. OTC – this includes medicinal preparation that does not require prescription. These can be sold to the general public. i. Example: analgesic – ASA, APAP b. Prescription Drugs – aka ethical drugs or medicinal products requiring the prescription of the physician, dentist, or veterinarian. All prescription drugs bear the Rx symbol on their label. i. Example: antibiotics, tranquilizer (Ativan, Valium, Librax, Artane) c. Dangerous Drugs i. Prohibited Drugs – which are the narcotics, and their synthetic derivatives and hallucinogens. Example: codeine, demerol, morphine & its derivatives, heroin, pantopen, cocaine d. Regulated Drugs – which are non-narcotic psychotropic drugs. i. Examples: 1. Amphetamine such as dexedrine & Benzedrine 2. Barbiturates – Luminal, phenobarbital 3. Meprobamates such as equanil, tranquilax 4. Methaqualone – Ex. Mandrax 5. Non-barbiturates (Hypnotic & sedative) such as Noctec, paraldehyde. III. According to Dosage Form SYRUPS POWDERS INJECTABLES Lozenges (Pastilles & Troches) Capsules Ointment Solutions Emulsions Suspensions Pill Sprays Tablets Lotions Aerosols Suppositories IV. According to Source of Basic Raw Material a. Synthetic drugs – ex. Coal and petrochemical derivative b. Plant-derived drugs – ex. Caffeine, quinine, and morphine c. Animal-derived drugs – ex. Adrenaline, liver extract d. Vaccines and Sera – ex. Prophylactic vaccines, antitoxins, antivenoms e. Bacteria for Antibiotic and Fermented products – ex. Chloramphenicol, gentamicin, tetracycline, penicillin, streptomycin HOW DO DRUGS REACH THE CONSUMERS? ● Drugstore – which amounts for 78% of total sales ● Private Hospitals & Industrial Outlet – 11% ● Government Hospitals/Agencies – 8% ● Physician – 3% WHAT PREVENTS US FROM SETTING UP A BASIC DRUG INDUSTRY? ● There’s no organic chemical industry to produce the raw material for drug production. ● Technology for drug production is costly or uneconomical for small countries like the Philippines. ● The local market is small and restricted to support a basic drug industry (low income & high drug prices are the main reasons). ● Multinational company WHAT PREVENTS US FROM SETTING UP A BASIC DRUG INDUSTRY? ● Massive Promotions ○ Price – (Drugs which are promoted effectively command a premium in price over unadvertised products).
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on ○ Drug companies also maintain strong links with medical societies and sponsor conferences, providing physicians with all kinds of amenities. ○ They develop good relationships with pharmacists & wholesalers by giving them trade deals and incentives, volume discount product samples, pin money, and other gift items. DO DRUG COMPANIES ENGAGE IN UNETHICAL MARKETING PRACTICES? ● Expensive marketing activities ● Marketing promotions inessential and hazardous ● Providing inadequate or false information on the product THE GOVERNMENT AGENCY THAT REGULATES THE DRUG INDUSTRY ● FDA Philippines formerly BFAD was created under RA 3720 (1963) as amended by Executive Order No. 175 (1987) and vested with the authority to administer and enforce pertinent laws, rules, and regulations. GOALS AND OBJECTIVES ● To ensure safety, efficacy and quality of processed foods, drugs, cosmetics, diagnostics agents, medical devices, and household hazardous substances. ● FDA also ensures the quality and truthfulness of information about these products labels, advertisement, and promotional materials. THE GOVERNMENT AGENCY THAT REGULATES THE DRUG INDUSTRY ( FDA) ● Inspection and licensing of establishments such as manufacturers, traders’ distributors, importers, exporters, wholesalers, and retailers. ● Evaluation, testing, and registration of products. ● Approval of product labels prior to commercial distribution. ● Monitoring of product advertisement and promotional materials. ● FDA Director: Dr. Samuel Zacate CONCEPTS OF PHARMACEUTICAL MANUFACTURING ● All pharmaceuticals are manufactured to rigorous regulatory standards to ensure that the products reaching patients are safe, effective and of a high quality. Developing sustainable product involves a number of different stages with pharmaceutical company: ○ Formulation ○ Process development ○ Analytical development ○ Regulatory ○ Quality control ● Clinical trials During the development of the drug, the formulation and process development groups liaise closely with the analytical development group. ● It is the responsibility of the analytical development group to develop suitable analytical methods for the testing of all components used in the manufacture of a drug product as well as the testing of samples both during and after manufacture. ● A wide variety of tests are employed to assess the quality of the product. ● Stability studies are conducted to determine the shelf-life of the product. ● The analytical development group in conjunction with the formulation development group determines specifications and tests that demonstrate that a quality product has been prepared. ● Once a suitable product is developed, the manufacturing process is transferred to the production group for routine manufacture and the analytical methods are transferred to Quality Control (QC) ● A manufacturing process typically has a large sequence step, involving several different unit operations (heat extinguishers, reactors, separators, etc.,) 3 BASIC LEVEL OF TOP MANAGEMENT AND THEIR FUNCTIONS ● LEVEL1 BOARD OF TRUSTEES OR BOARD OF DIRECTORS Functions: ○ To protect and make the most effective use of a company's assets. ○ To establish objectives and determine the basic policies and general course of the business. ○ Represents and safeguards stockholders. ● LEVEL II PRESIDENT Functions: ○ Management or administrative This includes: ■ Active planning ■ Direction ■ Coordination ■ Control of the business with the scope of policies established and authorized by the board or Level 1 ● LEVEL III ○ Vice-president ○ General managers ○ Department Managers ● Functions: ○ Management of the major departments of the company 2 FORMS OF ORGANIZATIONAL STRUCTURE ● FUNCTIONAL STRUCTURE ○ Groups all activities on the basis of similarity of the functions alone. ○ This is more appropriate for a small company or one with closely related products. ● DIVISIONALIZED STRUCTURE ○ The divisionalized structure combines into one unit, all different kinds of work necessary to accomplish specific results. ○ The kinks of work necessary may be grouped on geographical basis or more commonly on a product basis. LINE AND STAFF LINE ● LINE ○ Constitutes the framework for the organizational chart structure. ○ As a “chain of command” from the top and bottom of the organization.
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on
- Raw Materials a. Quarantined Area - This implies that the materials are subject to test and assays by the quality control section, and are not yet to be used. i. Labeled with a yellow coded labels bearing the word “ Quarantine” b. Approved for Use Area - The materials from the Quarantine Area found to conform to the standard and specification are transferred to this area, replacing the Quarantine label with the approved for use. i. Labeled with the green coded labels with bearing the word “ Approved for Use” c. Rejected Area - Are those found to be substandard and are transferred from the quarantine area to the Rejected Area. i. These materials are either returned to the supplier for replacement or disposed of properly. ii. Labeled with the red coded labels with bearing the word “ Rejected”
- In Process a. This section consists of products which has been bottled, stripped or packed but not yet labeled or packed into boxes or cartons, because they still await the results of the Quality Control test and assays as well as the final disposition. b.
- FInished Goods a. This area contains the products packaged and finished and are ready for distribution and sale.
- Returned Goods a. In as much as returned can not be avoided, the product returned are stored in this section by the Warehouse pending disposition by the Quality Control
- Dispensing a. Where raw materials for use in the production are weighed and measured b. The packaging materials are also counted upon issuance. ENGINEERING AND MAINTENANCE DIVISION ● Takes charge of the care, maintenance and repair of all machines and equipment used in the plant department ● Including: ○ Electrical lines ○ Water and Sewage systems ○ Waste Management ○ Telecommunication Lines ○ Environmental Sanitation. MANUFACTURING DIVISION The general procedure for the manufacture of a product is as follows
- The parent company abroad or the Research dept. locally prepares the Master Formula ( MF) then passes it onto its subsidiaries for the product manufacture. a. The Master Formula consists of the following information : i. Name of the Product ii. Potency of the Active Ingredient iii. Batch size: AMount of Yield iv. List of Ingredients and specifications, including code numbers v. Quantity of each ingredient vi. Signature of competent people who prepared the MF. b. The Quality Control head is in-charge of the preparation of the Maser Formula if the MF is not the actual amount to be transferred.
- The Production Contro l prepares the Manufacturing Order ( MO ) based upon the Master Formula of a required batch.
- The M.O contains the additional information as the scheduled date of production and the M.O number.
- The M.O is prepared in duplicate copies. One copy goes to the dispensing section of the Warehouse and the original copy goes to the Production Area. a. Together with the M.O is the Finishing Order ( F.O.) form. Which contains the list of packaging materials with the corresponding quantity necessary for the batch size indicated in the M.O.
- The Pharmacist in the Dispensing area weighs/measures the ingredients, counts the packaging material and transfers them to the manufacturing area and the packaging area respectively.
- The Manufacturing section compounds the product according to the standard compounding procedures for which they are provided with the copy.
- While the product is processed it undergoes an i n-process test by the Quality Control.
- The Compounded product is transferred to the packaging section where it is bottled, stripped or packed.
- The Packaging section transfers the bottled, stripped or packed products to the In-process area of the warehouse, pending the release of the final Quality Control test results.
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on
- If the in-process tests are approved by the Quality Control, the bottled, stripped or packed products are labeled, packed into the unit boxes the to cartons by the packaging section.
- The finished products are transferred in the Finished goods area of the Warehouse ready for distribution and sale. ● A cleanroom is a room in which the quantity and size of airborne particles are controlled in order to limit contamination. ● A cleanroom constructed and operated in a manner to control the introduction, generation, and retention of contamination inside the space. ● High Efficiency Particulate Air ( HEPA) Filters TWO TYPES OF CLEAN ROOM ● Hard wall – sturdy, stiff walls ● Soft wall – Flexible walls with plastic sheets DIRECTION OF AIRFLOW ● Horizontal: air moves parallel to the floor across the room ● Vertical: air moves from the top of the room down ISO STANDARD 14644 Least Clean ISO CLASS 9 ISO CLASS 8 ISO CLASS 7 ISO CLASS 6 ISO CLASS 5 ISO CLASS 4 ISO CLASS 3 ISO CLASS 2 ISO CLASS 1 Most Clean PROHIBITED ACTIONS ● Smoking ● Applying Makeup ● Eating ● Drinking ● Chewing gum/tobacco
PROCESS VALIDATION
VALIDATION
● Validation is defined as the verification by data and analysis of the design objectives of a given Facility, System. Apparatus, or Procedures are reliably fulfilled in routine operation. ● A validated product is one that has been shown by appropriate scientific means to be uniform within a lot, consistent between lots, and meeting design criteria within defined limits. ● Validation involves the following important steps: ○ Choosing the desired attributes of the products ○ Determining specifications for those attributes. ○ Selecting appropriate process and equipment. ○ Monitoring and testing processes, equipment and personnel while in operation. ○ Examining test procedures themselves to ensure their accuracy and reliability.
VALIDATED PRODUCT
● Is the one that has been shown by appropriate scientific means to be Uniform within a lot, Consistent between lots, and Meeting design criteria within defined limits. VALIDATION INVOLVES THE FOLLOWING IMPORTANT STEPS
- Choosing the desired attributes of the products
- Determining specification for those attributes
- Selecting appropriate processes and equipment
- Monitoring and testing processes, equipment and personnel while in operation
- Examining test procedures themselves to ensure their accuracy and reliability. SCOPE OF VALIDATION I. Process Validation II. Assay Validation III. Qualification of Manufacturing Equipments IV. Validation of existing products by statistical evaluation V. Cleaning Validation PROCESS VALIDATION ● CGMP's control procedures should be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. ● Process Validation is the gathering and documenting of sufficient evidence to give reasonable assurance that the process under review does what is purports and is expected to do. ● A means of ensuring that manufacturing processes are capable of consistently producing a finished product of the required quality. ● It involves providing documentary evidence that key steps in manufacturing process are consistent and reproducible ● A validated manufacturing process is one that has been proven to do what its purpose or is presented to do. FOR INSTANCE, IN TABLET MANUFACTURING, THE PROCESS SELECTED AND EVALUATED ARE:
- BLENDING OPERATIONS ● Optimal blending time ● Objective of blending- addition of lubricant or active ingredient ● Time when mixing does occur. ● Physical characteristics of powder blend ● Effect of load on blending ● Influence of process on dissolution
- WET GRANULATION ● Evaluation of binder ● Concentration required versus solubility in granulating solution
- EVALUATION OF MIXED GRANULATION ● Optimal density for powder flow ● How much granulating solution is required to ● effect a good granulation c. Compatibility of wet granulation. ● Optimal mixing time ● Effects of on dissolution or other physical/ chemical properties
- EVALUATION OF THE DRYING STEP AND DRIED GRANULATION ● Optimal moisture content ● Particle size distribution ● Any requirement for milling ● What conditions are required for optimal drying? EVALUATION OF MILLING THE GRANULATION ● Moisture pick-up vs % RH ● Compression qualities (Without lubricant) ● Granule disintegration characteristics
- TABLET COMPRESSION ● Compression force required
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on ● The FDA recommends that monitoring and sampling at the level determined during the process qualification stage be pursued until sufficient data is available. ● Maintenance of the facility, utilities, and equipment should not be overlooked. Through careful design (qualification) and validation of both the process and its control systems, a high degree of confidence can be established that all individual manufactured units of a given batch or succession of batches that meet specifications will be acceptable. PROCESS VALIDATION "REALLY ALWAYS THREE BATCHES?" "Safe, effective and reliable"
As a general rule, anything that can affect patient safety or
product quality should be validated including the following:
● Processes - such as manufacturing processes that produce a product ● Manufacturing Steps - each step may be validated separately for long processes ● Analytical Test methods - applicable for raw materials, intermediates, active pharmaceutical ingredients, finished pharmaceutical products, methods used for stability studies and those methods used in quality control. ● Systems and Programs - including those that support Good Manufacturing Processes (GMP) such as facility (building specifications), utilities, programs like pest control, software, hardware (enterprise Resource Platform) and laboratory information management systems and water for injection. ● Facilities - including rooms and equipment used for processing products that are sterile must adhere to strict criteria and be validated before use. ● Cleaning processes - including sterilize in place and clean in place TYPES OF PROCESS VALIDATION ● Prospective Validation ○ means validation done during the development stage. ○ During this step the input resources are selected and clearly specified. Each step in the development of a new manufacturing process is required to be established to give a desired result. ○ The approach in this validation often leads to transfer of the manufacturing process from the development function to production. ○ Examples ■ clearly defined material specification; ■ defined equipment and process parameter; ■ specified operating condition, if there is any; ■ defined level of training of people ● Concurrent Validation ○ carried out during production. ○ Extensive testing & monitoring ensure the desired quality characteristics of the product with high degree of confidence. ○ In this type, verification of process still goes on after three initial commercial batches are taken and the process is handed over to manufacturing personnel. ○ batch after batch, the process parameter is evaluated for manufacturing facilities and studied if any change or deviation is observed. ● Retrospective Validation ○ is used for facilities, processes and process control parameters used in operation that have not undergone a documented validation process but it is possible using historical data (QA/QC records) to provide the necessary documented evidence that the process is doing what is believed to do. ○ This type of validation is only acceptable for well established processes. ● Revalidation ○ is a repetition of the validation process and it is required under the following circumstances: ■ major changes in critical process parameters of formula, equipment, procedures, or quality of raw material or even in physical variation of raw material like particle size, changes in facilities and installation which influence the process.
EQUIPMENT VALIDATION
● Equipment Validation is a detailed process of confirming that an instrument is installed correctly, that it is operating efficiently, and that it is performing without error. ● Equipment validation is a documented process demonstrating whether a piece of equipment, system, or process consistently produces results within predefined specifications. ● This process ensures manufacturing equipment performs reliably and consistently, leading to the production of high-quality drugs. EQUIPMENT VALIDATION IS DIVIDED INTO THREE PARTS:
- Installation qualification (IQ) is the first step where a documented verification process that the equipment has been properly installed and configured according to industry and regulatory standards set by an approved installation checklist by the manufacturer. a. First, the equipment item is checked to be sure that it meets its design and purchase specifications and is correctly installed. b. Installation qualification includes, checking instruction manuals, schematic diagrams, and spare parts lists are present; checking that all components of the device are installed; checking that the materials used in construction were those specified; and making sure that fittings, attachments, cables, plumbing, and wiring are properly connected. c. IQ is documented proof that the equipment meets the design intention
- Operational qualification(OQ) is the next step and involves testing the equipment and making sure it performs within operating ranges as listed by the manufacturer. a. All aspects of the equipment receive individual testing and the tester documents the proper operation of each. b. After installation, the equipment can be tested to verify that it performs within acceptable limits. c. For example, an autoclave might be tested to see that it reaches the proper temperature, plus or minus certain limits, in a set period; that it reaches the correct pressure, plus or minus certain limits, etc. The penetration of steam to all parts of the chamber, the pressure achieved at various settings, and so forth,
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on would all be tested in the context of the operational qualification of an autoclave. d. OQ is documented proof that the equipment performs as specified
- Performance qualification (PQ) is the last step that ensures the equipment is fully qualified. a. In this step verification and documentation that all equipment is working within the accepted range as specified and should perform as expected under real conditions. b. A detailed test plan or protocol should test the equipment that can competently generate reproducible results c. Once all measuring instruments are calibrated, and all equipment is validated, process validation (or qualification) can be performed. d. The validation of the process will involve assessing the process under all the conditions that can be expected to occur during production. e. Testing includes checking the process endpoint(s) under these conditions and establishing that the process consistently meets its specifications. f. PQ is documented proof the equipment or systems operate as intended under challenge conditions. MANUFACTURING EQUIPMENT
- Scales and Balances
- Thermometers and Temperature Probes
- In-Process Moisture Tester
- Blenders and Mixing Equipment (Rotating Speed)
- Tablet Hardness Tester
- Disintegration Apparatus e.g. "Cycle" rates and water bath temperature
- Tablet Friabilator
- Mills, e.g. Mill speed
- Homogenizer
- Filter a. Normal clarification b. Sterilization filters c. HEPA filters
- Viscometer a. Rotor speed vs. setting b. thermometer certification Based on current government regulations, new facility construction, and internal policies, validation priorities were established to reflect: ● Sterile products ● Solid dosage forms ● Liquid products ● Packaging facilities WHY IS VALIDATION IMPORTANT IN MANUFACTURING? ● To ensure that a specific piece of equipment or process gives the output desired, the equipment used for the product must be validated. ● Equipment used for testing or manufacturing must be validated due to the risk it may propose to the product or end- user BIOMANUFACTURING VALIDATION ● There are three main areas of validation for a biomanufacturing facility. Validate the process, equipment, and methods. ● The planning of validation occurs throughout the development of the product. ● The actual validation process is usually performed before large-scale production and marketing of a product begins. ● Revalidation is required whenever there are changes in raw materials, equipment, processes, or packaging that could affect the performance of the product. ● The advantage of validation is that it helps to assure consistent product quality, greater customer satisfaction, and fewer costly product recalls. WHAT IS THE PROCESS? There are several steps involved in the validation process for manufacturing and laboratory equipment, which typically include the following:
- Planning. The first step in the validation process is to plan out the validation process, including identifying the equipment to be validated, the objectives of the validation, and the methods and criteria used to evaluate the equipment. Refer to your Validation Master Plan (VMP) for planning which our consultants can develop for you
- Installation Qualification (IQ). This step involves verifying that the equipment has been installed correctly and is operating according to the manufacturer's specifications.
- Operational Qualification (OQ): This step involves testing the equipment to ensure it can perform its intended functions consistently and accurately.
- Performance Qualification (PQ): This step involves testing to verify that the equipment can produce products that meet the required quality standards
- Ongoing monitoring and maintenance: Once the equipment has been validated, it is important to monitor it regularly to ensure that it continues to operate correctly and produce reliable results. This may include regular calibration and maintenance of the equipment. The very serious consequences of product failure has led to increased emphasis on validation of equipment. CGMP has pointed out the significance of calibration of such equipment at regular intervals of time to maintain its efficiency. VALIDATION OF EXISTING PRODUCTS BY STATISTICAL EVALUATION ● Validation is a key process for effective Quality Assurance. THE MAJOR REASONS FOR VALIDATION ARE: ● Quality Assurance ○ Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides a high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch. ● Economics ○ to successful validation, there is a decrease in sampling and testing procedures and there are less number of product rejections and retesting. This leads to cost-saving benefits. ● Compliance: ○ For compliance to current good manufacturing practices, validation is essential. PRODUCT VALIDATION ● Product validation is associated with validation of the full-scale manufacture of numerous earlier aspects of product development that are critical to the subsequent phases of the process. ● Product validation involves following steps: ○ validation of raw materials ○ validation of excipients. ○ validation of analytical methods ○ validation of finished product
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on a. Analysis of Variance b. Tolerance Limits
CLEANING VALIDATION
● Contamination is a critical factor leading to a product failure. ● For this reason, cleaning procedures must be adequate as well as effective. ● Cleaning validation is a procedure of establishing evidence that cleaning processes for manufacturing equipment prevents product contamination. ● Cleaning validation should be properly documented to demonstrate Current Good Manufacturing Practice (CGMP) for finished pharmaceuticals ● Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by: ○ other pharmaceutical products or APIs, ○ cleaning agents, ○ Micro-organisms ○ other materials (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). ● To avoid contamination, adequate cleaning procedures are critical. ● Cleaning procedures must strictly follow carefully established and validated methods of execution. ● This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients. ● In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level. ● The objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase. 3 PHASES OF CLEANING VALIDATION PROGRAM
- Pre-Validation - to evaluate the cleaning, sampling and analytical testing procedures.
- Validation to establish that the cleaning results are repeatedly acceptable.
- Revalidation- to ensure continuing validity of the cleaning procedures. 5 STEPS TO CLEANING VALIDATION Cleaning Validation at its simplest level can be broken into the following steps:
Step 1: Develop a cleaning validation protocol:
● The first step is to develop a protocol that outlines the cleaning procedures, including the cleaning agents, equipment, and personnel involved. ● The protocol should also include the acceptance criteria for the cleaning validation process.
Step 2: Conduct a risk assessment
● Before cleaning validation begins, a risk assessment should be conducted to identify potential sources of contamination. ● This will help to determine which areas of the facility require the most attention during the cleaning process.
Step 3: Clean and sanitize the facility
● The next step is to follow the cleaning protocol and thoroughly clean and sanitize all equipment and surfaces. ● This should be done by trained personnel and in accordance with the cleaning agent's manufacturer's instructions.
Step 4: Conduct testing
● Once the cleaning process is complete, samples should be taken from various areas of the facility and tested to ensure that the acceptance criteria have been met. ● The samples should be analyzed for the presence of any contaminants and the results should be documented.
Step 5: Review the results
● The final step is to review the results to ensure that the facility meets regulatory guidelines and industry standards for cleanliness and sanitation and make any necessary adjustments to the cleaning protocol. ● The cleaning validation process should be repeated on a regular basis to ensure that the facility remains in compliance with regulatory guidelines CLEANING VALIDATION STEPS
- Identify product, equipment and process
- Calculate limits and prepare cleaning method
- Collect swabs and rinse
- Recovery study
- 5Inspect visually
- Confirm effectiveness
- Validate cleaning ● Cleaning validation is necessary because it helps to ensure the safety and efficacy of the products being produced. ● Equipment and facilities are often used to produce multiple products, and if the equipment is not properly cleaned and sanitized between production runs, it can lead to cross- contamination. ● This can lead to product defects, recalls, or even harm to patients. ● Cleaning validation also helps to ensure compliance with regulatory guidelines. ● Both the pharmaceutical and medical device industries are heavily regulated, and facilities are required to follow strict guidelines for cleanliness and sanitation to prevent contamination. ● Cleaning validation helps to demonstrate that the facility is in compliance with these guidelines and is taking the necessary steps to prevent contamination. ● Most regulatory agencies and industry bodies publish guidelines on how to conduct cleaning validation.
Their principles could be summarized as follows:
- Cleaning validation should be a part of a pharmaceutical company's overall quality system and it should be based on a scientific rationale.
- A risk assessment should be conducted to identify potential sources of contamination.
- The cleaning process should be validated to ensure that it is effective in removing these contaminants.
- Cleaning validation should be performed on a regular basis and the results should be documented and kept on file
QUALITY BY DESIGN
● Quality by design (QbD) is a concept first developed by the quality pioneer Dr. Joseph M. Juran believed that quality should be designed into a product, and that most quality crises and problems relate to the way in which a product was designed in the first place. ● The concept of QbD was mentioned in the International Council for Harmonization (ICH) Q8 guideline, which states that “quality cannot be tested into products i.e., quality should be built in by design.” ● According to ICH Q8 QbD is defined as a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
Lecturer : Dr. Susan S. Montemayor Transcribed By : Julia Marie Babayen-on ● This involves designing and developing manufacturing processes during the product development stage to consistently ensure a predefined quality at the end of the manufacturing process. ● It emphasizes product and process understanding and process control which is based on sound science and quality risk management (QRM).
Quality by Design (QbD) has become a new concept for
development of quality pharmaceutical products:
● It is an essential part of the modern approach to pharmaceutical quality, QbD is a best solution to build a quality in all pharmaceutical products but it is also a major challenge to the Pharmaceutical industry whose processes are fixed in time, despite inherent process and material variability ● Under this concept of QbD throughout designing and development of a product, it is essential to define desired product performance profile or Target product Profile (TPP), Target Product Quality Profile (TPQP)] and identify critical quality attributes (CQA). ● On the basis of this we can design the product formulation and process to meet the product attributes. ● This leads to recognition of the impact of raw materials [critical material attributes (CMA), critical process parameters (CPP) on the CQAs and identification and control sources of variability. ● QbD is an emerging idea which offers pharmaceutical manufacturers with increased self-regulated flexibility while maintaining tight quality standards and real time release of the drug product. ● QbD is: ○ A Quality System for managing a product’s lifecycle ○ A regulatory expectation ○ Intended to increase process and product understanding and thereby decrease patient risk ○ A multifunctional exercise ● Principle of QbD Concepts include risk and knowledge based decisions, systematic approaches process development, continuous Improvement, and this leads to “capable” processes.
ADVANTAGES OF QUALITY BY DESIGN
- Higher level of product and process understanding, which can lead to: a. Increased success rate in development and manufacturing b. Increased process robustness, less manufacturing deviations and failed/reworked batches
- Potential regulatory flexibility, which can lead to: a. Ease of post approval changes for movements within an approved design space. b. Real time release testing (RTRT) resulting in lower analytical testing costs, lower cycle times, etc
REASON/PURPOSE FOR VALIDATION
- Enables scientist to communicate scientifically and effectively on technical matters
- Setting standards of evaluation procedures for checking compliance and talking remedial measures
- Economic - Reduction in cost associated with process sampling and testing
- As quality of product cannot always be assured by routine quality control because testing statistically insignificant number of sample, The Validation thus shall provide adequacy and reliability of a system or a procedure to meet the predetermined criteria/ attributes providing high degree of confidence that the same level of quality is consistently built into each unit of finished product from batch to batch
- Retrospective validation is useful for trend comparison of results and compliance to CGMP/CGLP
- Closer interaction with pharmacopeial forums to address analytical problems. 7. International pharmacopoeial harmonization particularly in respect of impurities determination and their limits. 8. For taking appropriate action in case of Non-compliance.
VALIDATED ANALYTICAL INSTRUMENT
QUANTITATIVE ANALYSIS OF DRUGS IN PHARMACEUTICAL
FORMULATIONS
● “One of the most frustrating aspects for an analyst is working with an ill-defined, poorly designed, and invalidated analytical method.
- As simple as Possible
- Most Specific
- Most Productive, economical, and Convenient
- As accurate and precise as required
- Multiple sources of key components ( reagents, Columns, TLC plates) should be avoided.
- To be fully optimized before transfer for validation of its characteristics such as accuracy, precision, sensitivity, ruggedness, etc.
ANALYTICAL PARAMETERS TO BE VALIDATED
- Accuracy a. It is expressed as % recovery by the assay of known/ added amount of analyte in the linearity range b. It can also be determined by comparing the results with those obtained using an alternative method which has already been validated
- Precision a. It expresses a degree of agreement among individual test results when procedure/method is applied to homogenous sample b. It is usually represented as SD/RSD c. It is a measure of degree of repeatability or reproducibility under normal conditions
REPEATABILITY ( UNDER SAME CONDITION )
● Precision of the method when repeated by the same analyst, same test method and under the same set of laboratory conditions ( reagent, equipment, etc. ) within a short interval of time, the only difference being the sample.
REPRODUCIBILITY ( UNDER DIFFERENT CONDITION )
● When the subject method is carried out by different analysts in different laboratories, using different equipment reagents, and laboratory settings and on different days-variability of analytical results as function of analyst, day-to-day, laboratory to laboratory, equipment to equipment, etc. using the sample from the same homogeneous batch.
INTERMEDIATE PRECISION
● Within the same laboratory but different days, analyst, equipment and reagents.
- Selectivity ( Specificity )
