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MANUFACTURING PHARMACY (LEC) DRUG (RA 9711) (1) Articles Recognized In Official pharmacopeias and formularies, incl...

MANUFACTURING PHARMACY (LEC) DRUG (RA 9711) (1) Articles Recognized In Official pharmacopeias and formularies, including official homeopathic pharmacopeias, or MANUFACTURING any documentary supplement to any of - Large scale production of drugs them, which are recognized and adopted - Includes preparation of drugs, packaging, by FDA repacking, or changing the container, (2) Articles intended for use in the diagnostic, wrapper or label of any drug in preparation cure, mitigation, treatment, or prevention for distribution. of disease in man or in animals (3) Articles (other than food) intended to affect DRUG the structure or any function of the body of - Articles intended for use in the diagnosis, man or animals cure, mitigation, treatment, or (4) Articles intended for use as a component prevention of disease in man or in of any articles specified in clause (1), (2), animals or (3) but do not include devices or their - Articles (other than food) intended to affect components, parts or accessories. the structure or any function of the body of man or animals MANUFACTURING ACTIVITIES Primary manufacturing MANUFACTURING COMPOUNDING - API and Excipients Large scale Small scale Secondary Manufacturing - Pharmaceutical Products/Dosage forms Manufacturing order Prescription order General Specific Tertiary Manufacturing - Packaging, Labeling, and Repacking of Manufacturing Community/Hospital bulk finished products establishment pharmacy DRUG ESTABLISHMENTS Products Preparations Any organization or company involved in the Expiration date Beyond-use date manufacture, importation, repacking and/or distribution of drugs or medicines DRUG (RA 3720) (1) Articles recognized in the current edition of AO 2014-0034 - Revised rules USP-NF official homeopathic pharmacopoeia of the US, official national 1. Drug Manufacturer Drug formulary, or any supplement to any - any establishment engaged in operations of them involved in the production of drugs (2) Articles intended for use in the diagnostic, a. Ethical manufacturers cure, mitigation, treatment, or prevention – Prescription of disease in man or in animals b.Proprietary/generic manufacturers (3) Articles (other than food) intended to affect –branded/generic the structure or any function of the body of c.Biologicals manufacturers man or animals –vaccines/toxoids/antisera (4) Articles intended for use as a component d. Veterinary products manufacturers of any articles specified in clause (1), (2), – animal drugs or (3) but do not include devices or their e. Medicinal chemical manufacturers components, parts or accessories. – AI/excipients MANUFACTURING PHARMACY (LEC) f. Toll/contract manufacturers I. ORGANIZATIONAL PLANNING – drugs for other companies - Interpreted in a chart - Only involve in the packaging Packer - Involved on packaging of bulk Characteristics of an Organizational Chart products to its immediate container 1. It lists all important positions and Repacker - involved in repacking of the functions of each divisions or products into smaller quantities in department separate containers or smaller quantities 2. It is a means of quickly showing and/for secondary packages the shape or structure of the company to employees and other 2. Drug Distributor / Importer / Exporter interested parties outside the - Imports or exports raw materials, active company. ingredients or finished products for its own use or for wholesale distribution on Importance of a Chart wholesale basis 1. Can analyze organizational problems like overlapping of 3. Drug Trader functions - registered owner of the drug product but 2. Can assess the strengths and subcontracts toll manufacture of such weaknesses in the functions and products to a licensed manufacturer personnel 3. Can plan changes in the structure, 4. Drug Distributor/Wholesaler if not applicable - Procures raw materials, active ingredients and or finished product from Some Drawbacks in the Chart local establishment or for local distribution 1. Cannot reveal company objectives on wholesale basis and policies - Cannot do Importation/Exportation 2. Cannot indicate a delegated authority 3. Reveals little about working relationships II. POSITION DESCRIPTION - Defines authority, duties, and ORGANIZATION responsibilities or the ares in the chart - Social unit of people that is STRUCTURES of MANAGED to meet a III. ORGANIZATIONAL MANUAL need or to pursue collective goods. - A.k.a. Management guide - - Combines the chart and position BASIC ELEMENTS OF AN ORGANIZATION descriptions, with description materials 1. Division of responsibility/obligation/duty about organization 2. Delegation of authority 3. Determination of the interrelationship BASIC LEVELS OF MANAGEMENT among functions of each organizational components LEVEL 1 - “Board of Trustees” BASIC TOOLS IN AN ORGANIZATION - Protects and makes the most effective use I. Organizational Planning of the assets of the company II. Position Description LEVEL 2 III. Organizational Manual - “President of the Company” - General management of the business MANUFACTURING PHARMACY (LEC) - Active planning, direction, coordination, 2. Applied research and control of the business - Chemical studies, development of LEVEL 3 chemical process - “Vice-Presidents, general managers and 3. Clinical Research stage department managers” - Manufacturing requirements, - Management of the major costing, product control, patent divisions/departments of the company. application FORMS AND ORGANIZATIONAL STRUCTURE 1. Functional structure - It groups all activities on the basis of functions alone. 2. Divisionalized Structure - It combines into one unit, all different kinds of work necessary to accomplish a specific result. PRODUCTION DEPARTMENT LINE - Deals with all stages of manufacturing - Identified as a chain of command from top batches of finished drug products to the bottom of the organization - Plans the production according to MO - Constitutes to framework of the - Accomplish the BMR to ensure the organizational structure batches were properly made, and tests were conducted STAFF - Constitutes the work functions or the PRODUCTION CONTROL SECTIONS organization component that are required Purchasing to supply information and services to the Inventory control “line” components Planning and scheduling MANUFACTURING COMPANY DEPARTMENTS WAREHOUSE DIVISION SECTIONS 1. Research and Development department Raw Materials Section 2. Production Control division Quarantined Area 3. Warehouse division Approved for use area 4. Quality Control Department Rejected Area 5. Marketing department In-Processed section 6. Regulatory department Finished Products section 7. Engineering & Maintenance section Returned Goods section 8. Medical department Dispensing section 9. Administration 10. Finance/Purchasing department 11. Quality Assurance department RESEARCH AND PRODUCT DEVELOPMENT Chemical research Biological research 3 STAGES FOR RESEARCH 1. Preliminary - Market search, literature review, QUALITY CONTROL patient search 1. Specifications and Assay development section MANUFACTURING PHARMACY (LEC) 2. Central release section - To conduct stability studies (real 3. Chemical control section time, long term, short term, stress 4. Plant inspection section test, accelerated) 5. Biological-microbiological section 4. PLANT INSPECTION SECTION 1. SPECIFICATIONS AND ASSAYS Functions: DEVELOPMENT SECTION - To inspect every shipment of raw Purpose: materials and every lot of finished - Conform to appropriate standards product of identify, purity, potency, quality, - To conduct stability studies physiological availability and - To inspect and check all therapeutic activity manufacturing operations, - Meet government rules and including in-process filling and regulations labeling a well as periodic - Prevent potential hazards to public examination on the quality of health stocks in the warehouse. - To sample retention or reserved 2. CENTRAL RELEASE SECTION sample withdrawn from the Function: packaging line for finished - To examine meticulously the products and from the warehouse records resulting from the exercise for raw materials of QC functions throughout all Retention/reserve samples: steps of manufacturing and - Are portions of material or finished packaging for completeness and products taken from the same lot accuracy and to assume tested and assayed are kept in responsibility for their safekeeping locked areas under the same and storage conditions comparable to market - To investigate customer complaints conditions. or inquiries on product quality - The quality of reserved samples since this section has an easy include at least 2 labeled easy access to records of containers of the final dosage form manufacturing and packaging or 2 times the quality required for operations testing. These samples are to be - To maintain complete and accurate retained for at least 2 years after records of the receipts and distribution or 2 years after expiry, distribution of every lot of ra whichever is shorter. material and finished product - To keep retention samples in 5. BIOLOGICAL-MICROBIOLOGICAL locked areas under similar SECTION conditions comparable to the Functions: market conditions - To perform and evaluate - To properly record and handle microbiological and finished products returned by pharmacological assays pharmacies and hospitals - To do sterility, pyrogen city, bacteriology. Irritation, and 3. CHEMICAL CONTROL SECTION safety/toxicity tests. Functions: - To test and assay every lot of raw material, in-process products and every lot of finished product MANUFACTURING PHARMACY (LEC) ▪ Component: any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such product ▪ In-Process Material: any material fabricated, ▪ Part of quality assurance which ensures that compounded, blended or derived by chemical medicinal products are consistently produced and reaction produced for, and used in the preparation controlled to the quality standards appropriate to of the drug product their intended use. ▪ Master Records/Batch Manufacturing ▪ It is designed to minimize the risks involved in Record: ensure that batches were properly any pharmaceutical production that cannot be made, and QC tests were performed (checklist, eliminated through testing the final product. actual yield); important parameters (e.g. mixing - First documented published in Canada speed, mixing time) ▪ Theoretical Yield: quantity that would be Main Risks: produced at any appropriate phase of ▪ unexpected contamination of products manufacturing based upon the quantity of raw ▪ incorrect labels on containers mats used; summation of ingredients or quantity ▪ insufficient or too much active ingredient ▪ Actual Yield: quantity actually produced at any appropriate phase of manufacturing, processing, QUALITY or packing ▪ Means “excellence” or “goodness”. ▪ Master Formula: contains formulations, ▪ Refers to attributes or characteristics of a manufacturing procedures, specifications, QA product which when compared to standard serves requirements and labeling of a finished product as basis for measuring its conformity and helps ▪ Monograph: document that specifies all the determine the degree of acceptability. tests to be conducted on a product and/or - QUALITY = EFFICACY + SAFETY appropriate references containing details of procedure and expected result ▪ Certificate of Analysis: document with the DEFINITION OF TERMS results of all tests conducted on material to show compliance or non-compliance with the standard ▪ Drug: intended for and having as their main use specs the diagnosis, mitigation, tx, cure, or prevention of ▪ Raw Material Specification: enumerate the disease in man and other animals characteristics of all the mats that go into the ▪ Pharmaceutical Preparation: means of product and the permissible range of purity of administering drugs as formulated preparations each ingredient ▪ Dosage Form: AI + additives ▪ Formula: concise and precise statement of the ▪ Drug Products: finished dosage form that ingredients that comprise the product together contains AI, generally, but not necessarily, in with the percentage and/or weight of each association with inactive ingredients ▪ Standard Operating Procedure: step by step ▪ Batch: specific quantity of a drug or other method on how to go about a job material intended to have uniform character and ▪ Finished Product Specifications: cover all quality characteristics that affect the proper performance, ▪ Lot: batch or a specific identified portion of a purity, safety and stability of the product batch ▪ Sample: finite number of objects selected from ▪ Active Ingredient (AI): any component a batch intended to furnish pharmacological activity ▪ Manufacturing Order: instructions to ▪ Pharmaceutical Excipients: any component Production dept to produce a product including other than the AI number of products at a given time ▪ Quarantine: area marked, designated or set ▪ Overage: addition of an API in an unstable prep aside for the holding of incoming components to compensate for loss during manufacture prior to acceptance examination ▪ Validation: documented evidence that a system does what it is supposed to MANUFACTURING PHARMACY (LEC) PHARMACEUTICAL QUALITY SYSTEM Philippine GMP regulation: Management system to direct and control a A.O. 43 s. 1999 pharmaceutical company with regard to quality. – adoption of the 1st edition of the current GMP guidelines by FDA. International Council for Harmonisation (ICH) ▪ an organization that brings together regulatory A.O. 2012-0008 authorities and pharmaceutical industry – adoption and implementation of the PIC/S GMP representatives from around the world to develop as the standard on the manufacturer. guidelines for the pharmaceutical industry FDA MC 2012 ICH Q10 - Pharmaceutical Quality system – Philippine FDA mandated all drug - All life cycle manufacturers to ensure strict and full compliance ▪ one of the internationally harmonized guidance to the newly adopted PICS intended to assist pharmaceutical manufacturers by describing a model for an effective quality PIC/s GMP management system for the pharmaceutical - Modified version of WHO - European industry, referred to as the pharmaceutical quality union system - Pharmaceutical Inspection Convention (PIC)s - PIC/s - Pharmaceutical Inspection Cooperation Scheme ▪ PIC/s GMP Guide Introduction ▪ PIC/s GMP Guide Part I – Basic Requirements for Medicinal Products ▪ PIC/s GMP Guide Part II – Basic Requirements for Active Pharmaceutical Ingredients (APIs) ▪ PIC/s GMP Guide Annexes *Certificate of GMP - need beore a company can manufacture II. ORGANIZATION AND PERSONNEL SECTIONS OF PIC/s GMP - authority and responsibility for all functions I. Pharmaceutical Quality System - All personnel have the training, education II. Personnel and/or experience III. Premises and equipment IV. Documentation V. Production GENERAL REQUIREMENT VI. Quality control VII. Outsourced activities ▪ Individual written job description VIII. Complaints and product recall ▪ Adequate authority to carry out responsibilities IX. Self-inspection ▪ No gaps or unexplained overlaps ▪ Organization chart I. PHARMACEUTICAL QUALITY SYSTEM ▪ Prevent unauthorized access to production, (PQS) storage, quality control ▪ Stop personnel who do not work in these areas QUALITY MANAGEMENT SYSTEM (QMS) using them as passageways A comprehensive system that outlines responsibilities, procedures, processes, and PERSONNEL resources for implementing quality management. ▪ People must have the knowledge and skills to perform their job. MANUFACTURING PHARMACY (LEC) ▪ They must have personal responsibility to Air locks/ changing rooms - interlocking develop personal competence through having system: it permits opening of one door at a time sufficient education, training and experience thereby reducing the chances of contamination ▪ Key personnel (normally full time) positions Step-over benches provides physical barrier include: between the area with proper segregation of ✓ Head of Production footwear and garments ✓ Head of Quality Control Mirror is to be provided at this point so as to ▪ Heads of Production and Quality Control should enable self viewing of the uniform and ensure that be independent of each other body parts, hair are properly covered CLOTHING ✓ Clean outer garments ✓ Hair nets / head coverings ✓ Employee uniforms No uncovered street clothes in production area Worn to protect product and equipment from employee’s clothes ✓ Clean footwear / overshoes ✓ Use locker facilities provided PERSONNEL DESIGN OF ATTIRE ▪ All employees must receive proper training in ▪ Personnel should wear clean attire appropriate the procedures relating to their job and in the to the duties they perform. cGMP regulations. ▪ Design of the attire should not have: PERSONNEL TRAINING ▪ fiber materials (lint-free) ▪ Personal Hygiene ▪ pocket at upper part of the waist ▪ Clothing ▪ Sew pockets shut if possible ▪ Workplace Guidelines ▪ Pens and other objects can fall out when ▪ Visible Illness and Open Lesions you bend over ▪ Health Examinations ▪ These items are often physical hazards ▪ They also carry bacteria DEFINItiONS OF TERMS ▪ Hygiene: conditions or practices conducive to WORKPLACE HABITS maintaining health and preventing disease, ▪ Prohibit use of jewelries in production area especially through cleanliness ▪ Hair combing is allowed only in the locker room. ▪ Personal hygiene: Refers to cleanliness of a ▪ Prohibit use of artificial eyelash, synthetic nail, person’s body and cosmetics ▪ Communicable disease: Pathogens ▪ Eat only in the lunchroom transmitted by one person to another – may be by ▪ Store your lunch in designated area touch/through food /by aerosols ▪ Don’t leave garbage lying around ▪ Don’t use uniform to clean hands GOOD PERSONNEL HYGIENE ▪ Don’t chew gum Personnel must practice good personal hygiene. ▪ Never sneeze into air ▪ regular bathing every day ▪ brushing of teeth VISIBLE ILLNESS & OPEN LESIONS ▪ washing hands ▪ Personnel who have an illness or open lesions that are likely to present a risk to the product, GOWNING should not be allowed to carry out operations ▪ provides barrier between personnel and the that involve handling of starting materials, product MANUFACTURING PHARMACY (LEC) intermediates or finished products until the ▪ Storage areas for approved raw material, condition has cleared up. packaging materials, and finished goods ▪ Personnel should be instructed and encouraged ▪ Quarantine & reject areas to report to their immediate supervisor when ▪ Processing they are ill or when they see any conditions that ▪ QC laboratory may adversely affect the product quality. ▪ Equipment washing ▪ Storage of idle, cleaned equipment HEALTH EXAMINATIONS ▪ Staging of bulk products ▪ Regular medical examinations ▪ Packaging/ labeling operations ▪ during recruitment process ▪ Storage of cleaning tools and supplies ▪ every regular period ▪ Annual Physical Examination EQUIPMENT ▪ Eye Examinations ✓ Design, locate and install equipment to suit its ▪ Allergen Test intended use ✓ Easy to clean, repair and maintain III. PREMISES & EQUIPMENT ✓ Suitable for its intended use - structure, spaces, design must be such to ✓ Not reactive, additive or absorptive enable thorough cleaning, inspection, safe and ✓ Calibrated at defined intervals effective use of equipment. ✓ Clearly labeled - Factors such as water quality, security on ✓ Equipment must be properly qualified ( Design, materials, separate areas for quarantine, Installation, Operation and Performance) rejected materials, for quality approval, for weighing, etc. IV. DOCUMENTATION - Most inert type of stainless steel - SS 316 Site Master File A document describing the GMP PREMISES related activities of the manufacturer. ▪ Must be designed and constructed to Instructions facilitate company productivity ▪ Specifications ▪ Adequate size and space for operations ▪ Manufacturing formulae, processing, packaging ▪ Facilities, equipments and utilities (water and testing instructions systems, electrical etc.) must be validated ▪ Procedures (Standard Operating Procedures or ▪ Good flow pattern for personnel, materials, SOPs) products and waste materials (flow from ▪ Protocols clean to dirty and vice versa) ▪ Technical Agreements ▪ Environmental controls must be in place Records/Reports (clean rooms) ▪ Records ▪ Parameters to control in the plant to reduce ▪ Certificates of Analysis risk of contamination from the environment: ▪ Reports ✓ Lighting ✓ Temperature LABELS ✓ Humidity Identity Labels ✓ Ventilation - placed on containers, vessels, equipment to ✓ Interior surfaces (walls, floors and ceilings) identify the material or product that is inside. ✓ Pipe work, light fittings and ventilation points ▪ Defined area for: Status Labels ▪ Receiving of starting & packaging - Are placed on containers, vessels and materials equipment to indicated current status (or ▪ Sampling condition) ▪ Weighing/dispensing - e.g. ▪ Gowning/ change room “QUARANTINE” “RELEASED” or MANUFACTURING PHARMACY (LEC) “APPROVED” “REJECTED” GENERAL GUIDELINES ▪ Record keeping requirements ▪ Black ink ▪ No white out ▪ Single line, Date, Initial ▪ No blanks ▪ N/A any lines which do not apply ▪ Legible ▪ To err is human. ▪ To destroy the evidence is a felony VIII. COMPLAINTS AND PRODUCT RECALL ▪ Maintain every record as if it were going to be reviewed by the FDA. CONTAMINATION ▪ Your signature is precious Our products can become contaminated by ▪ Never sign, approve, or authorize anything that makes them: anything you are not absolutely sure is impure correct. unclean; or unfit for use V. PRODUCTION ▪ PRODUCTION is defined as all activities CONTAMINANTS starting from processing to packaging to obtain 1. Products or substances other than product finished products manufactured ▪ PROCESSING is part of production cycle 2. Foreign products starting from weighing of raw materials to obtain a 3. Particulate matter bulk product 4. Micro-organisms ▪ PACKAGING is part of production cycle starting 5. Endotoxins (degraded micro-organisms) from bulk product to obtain the finished product ▪ STARTING MATERIALS consist of raw CROSS-CONTAMINATION materials and packaging materials used in the Cross-contamination is a particular case production of cosmetic products of contamination. Cross-Contamination is the presence in GENERAL GUIDELINES a particular product of small, traceable ▪ All incoming materials should be quarantined quantities of other pharmaceutical immediately after receipt until they are released products manufactured for use in production ▪ Storage of materials should be orderly to avoid CAUSES OF CROSS-CONTAMINATION mix up and cross contamination Can occur when containers are not tightly ▪ Ensure that there is an effective system in sealed. controlling stocks Ventilation system not properly filtered and ▪ Ensure that consumption of starting materials container not sealed tightly. follows : Powder left on scoop when weighing a ▪ FIFO ~ First-In-First-Out, or different component. ▪ FEFO ~ First Expiry, First Out. Equipment and machines are not properly cleaned. Incorrectly weighed or measured component. Mix-ups which cause incorrect components to be weighed out during dispensing. MANUFACTURING PHARMACY (LEC) Cross-Contamination specifications must be investigated whether or not Cross-contamination can be minimized by: the batch has already been distributed. 1. Personnel procedures 2. Adequate premises 3. Use of closed production systems 4. Adequate, validated cleaning procedures 5. Appropriate Levels of Protection of product 6. Correct air pressure cascade COMPLAINTS AND RECALLS Complaints ▪ All complaints and other information concerning potentially defective products must be carefully reviewed and investigated according to written procedures. ▪ Record of complaints and results of investigation must be kept for at least one year after the expiry date ▪ The entire Batch Processing Record and Batch Control Record must be reviewed ▪ The source and content of deficiencies, remedial measures taken and tests performed should be documented in writing and added to the batch records ▪ Consideration should be given to check if other batches could be affected and to cease supply until the problem is fully investigated ▪ Product recall should be initiated if deficiency is potentially harmful to health. Recalls Actions taken by a firm to remove from the market any product that is in violation of laws administered by the FDA. Recalls of a drug may be conducted on a firm’s own initiative or by FDA request. Deviation Investigations ▪ Any unexplained discrepancy or the failure of a batch or any of its components to meet any of its