CERTIFICATE

This is to certify that Project entitled GMP Guidelines submitted to B.R. Nahata College of Pharmacy, is a bonafide work carried out by Mr.Adarsh Sahu for the Diploma in Quality Assurance under my guidance during the academic year 2010-2011.

Mrs. Anurekha Jain H.O.D Pharmacognosy B.R.Nahata

Affectionally dedicated To My beloved Parents & Family

ACKNOWLEDGEMENT
Let me express my profound sense of gratitude and heart full thanks to my esteemed project guide Mrs. Anurekha Jain, for her tolerance in every step, keen interest, regular observations, kind co-operation, boundless enthusiasm, affectionate encouragement, simulative and constructive criticism, throughout this work has brought up this dissertation entitling "GMP Guidelines" into this shape. Words fail to express my real feelings of obligation regarding his cool mentality at much hard times. With pride and pleasure, I wish to express my thanks to H.O.D & faculty members of B.R.Nahata mandsaurfor his valuable help and providing me the necessary facilities to carry out this work with great ease and precision. I wish to offer my respectable thanks to him, for their support and encouragement throughout my dissertation work. At inception I am confessing to all my well-wishers, whose name not mentioned in these pages and I express my sincere thanks to all those who were instrumental both directly and indirectly in completing my dissertation work successfully.

Mr. Adarsh Sahu

Contents
1. Introduction

A. Objective B. Regulatory Applicability C. Scope

2. Good manufacturing practices (GMP) 3. QUALITY MANAGEMENT

A. Principles B. Responsibilities of the Quality Unit C. Responsibility for Production Activities D. Internal Audits (Self Inspection) E. Product Quality Review
4. PERSONNEL 4. Validation 5. Protocols 6. Master validation plan 7. Change control 8. Facility systems and equipment 9. Format for an installation qualification protocol

1. Introduction

Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods, pharmaceutical products, and medical devices. GMPs are guidance that outline the aspects of production and testing that can impact the quality of a product. Many countries have legislated that pharmaceutical and medical device companies must follow GMP procedures, and have created their own GMP guidelines that correspond with their legislation, basic concepts of all these guidelines remains more or less similar that is ultimate goal to safeguard the health of the patient, producing a good quality medicine or medical devices or active pharmaceutical products, in U.S the drug may be deemed by law as adultrated even if it passes all the specifications tests but is found to be manufactured in condition which violates current good manufacturing guidelines, therefore complying with gmp is a mandatory aspect in pharmaceutical manufacturing. Although there are a number of them, all guidelines follow a few basic principles.

Manufacturing processes are clearly defined and controlled. All critical processes are validated to ensure consistency and compliance with specifications. Manufacturing processes are controlled, and any changes to the process are evaluated. Changes that have an impact on the quality of the drug are validated as necessary. Instructions and procedures are written in clear and unambiguous language. (Good Documentation Practices) Operators are trained to carry out and document procedures. Records are made, manually or by instruments, during manufacture that demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the drug was as expected. Deviations are investigated and documented. Records of manufacture (including distribution) that enable the complete history of a batch to be traced are retained in a comprehensible and accessible form. The distribution of the drugs minimizes any risk to their quality. A system is available for recalling any batch of drug from sale or supply.Complaints about marketed drugs are examined, the causes of quality defects are investigated, and appropriate measures are taken with respect to the defective drugs and to prevent recurrence.

A. Objective This document is intended to provide guidance regarding good manufacturing practice (GMP) for themanufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. In this guidance, the term manufacturing is defined to include all operations of receipt of materials,production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendation

that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.mpany's responsibility to determine the most effective and efficient quality process.

This guidance document has been prepared to aid vaccine manufacturers in the preparation and performance of the validation studies required by Good Manufacturing Practices (GMP) of the World Health Organization (WHO). The WHO GMP publications,other GMP Regulations/Guidelines and many publications on the concept andprocess of validation for pharmaceutical manufacture were consulted during preparationof the Guide. B. Regulatory Applicability Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance. C. Scope This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities.

2. Good manufacturing practices (GMP) WHO defines Good Manufacturing Practices (GMP) as that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP covers all aspects of the manufacturing process: defined manufacturing process; validated critical manufacturing steps; suitable premises, storage, transport; qualified and trained production and quality control personnel; adequate laboratory facilities; approved written procedures and instructions; records to show all steps of defined procedures have been taken; full traceability of a product through batch records and distribution records; and systems for recall and investigation of complaints. The guiding principle of GMP is that quality is built in to a product, and not just tested

in to a product. Therefore, the assurance is that the product not only meets the final specifications, but that it has been made by the same procedures under the same conditions each and every time it is made. There are many ways this is controlled - validation is that part of GMP that ensures that facility systems, equipment, processes, and

tests procedures are in control and therefore consistently produce quality product.

3.Quality management A. Principles Quality should be the responsibility of all persons involved in manufacturing. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented. There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA andQC units or a single individual or group, depending upon the size and structure of the organization. The persons authorized to release intermediates and APIs should be specified. All quality-related activities should be recorded at the time they are performed. Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use

B. Responsibilities of the Quality Unit(s) The quality unit(s) should be involved in all quality-related matters. The quality unit(s) should review and approve all appropriate quality-related documents. the main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to: 1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the

control of the manufacturing company 2. Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials.

3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution. 4. Making sure that critical deviations are investigated and resolved 5. Approving all specifications and master production instructions 6. Approving all procedures affecting the quality of intermediates or APIs 7. Making sure that internal audits (self-inspections) are performed 8. Approving intermediate and API contract manufacturers 9. Approving changes that potentially affect intermediate or API quality 10. Reviewing and approving validation protocols and reports 11. Making sure that quality-related complaints are investigated and resolved 12. Making sure that effective systems are used for maintaining and calibrating critical equipment 13. Making sure that materials are appropriately tested and the results are reported 14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate 15. Performing product quality reviews

C. Responsibility for Production Activities The responsibility for production activities should be described in writing and should include, but not necessarily be limited to: 1. Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures 2. Producing APIs and, when appropriate, intermediates according to pre-approvedinstructions

3. Reviewing all production batch records and ensuring that these are completed and signed 4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded

5. Making sure that production facilities are clean and, when appropriate, disinfected 6. Making sure that the necessary calibrations are performed and records kept 7. Making sure that the premises and equipment are maintained and records kept 8. Making sure that validation protocols and reports are reviewed and approved 9. Evaluating proposed changes in product, process or equipment 10. Making sure that new and, when appropriate, modified facilities and equipment are Qualified

D. Internal Audits (Self Inspection) To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule. Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.

E. Product Quality Review Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least: A review of critical in-process control and critical API test results A review of all batches that failed to meet established specification(s) A review of all critical deviations or nonconformances and related investigations A review of any changes carried out to the processes or analytical methods; A review of results of the stability monitoring program A review of all quality-related returns, complaints and recalls

3. Validation
Validation is defined as the establishing of documented evidence which provides a high degree of assurance that a planned process will consistently perform according to the

intended specified outcomes. Validation studies are performed for analytical tests, equipment, facility systems such as air, water, steam, and for processes such as the manufacturing processes, cleaning, sterilization, sterile filling, lyophilization, etc. There will be a separate validation for the lyophilizer as an equipment item and for the lyophilization process; for the cleaning of glassware and the cleaning of the facility; and for the sterilization process and for the sterility test. Every step of the process of manufacture of a drug product must be shown to perform as intended. Validation studies verify the system under test under the extremes expected during the process to prove that the system remains in control. Once the system or process has been validated, it is expected that it remains in control, provided no changes are made. In the event that modifications are made, or problems occur, or equipment is replaced or relocated, revalidation is performed. Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control. The validity of systems/equipment/tests/processes can be established by prospective, concurrent or retrospective studies. Prospective validation is data collected based on a pre-planned protocol. This is the most controlled method and is the validation approach presented in this Guide.

4. PERSONNEL A. Personnel Qualifications) There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.

The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing. Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed.

B. Personnel Hygiene Personnel should practice good sanitation and health habits. Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination. Personnel should avoid direct contact with intermediates or APIs. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs. C. Consultants Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

5. Protocols
A protocol is a written set of instructions broader in scope than a Standard Operating Procedure (SOP). SOPs are the detailed written instructions for procedures routinely performed in the course of any of the activities associated with pharmaceutical manufacturing.

A protocol describes the details of a comprehensive planned study to investigate the consistent operation of new system/equipment, a new procedure, or the acceptability of a new process before it is implemented. Protocols include significant background information, explain the rationale for and the objective of the study, give a full description of the procedures to be followed, set out the parameters to be measured, describe how the results will be analyzed, and provide pre-determined acceptance criteria for making conclusions. Validation studies, stability studies, and clinical studies are examples of written protocols for pharmaceutical manufacturers. Validation protocols are important in ensuring that documented evidence is taken which demonstrates that an equipment item, a system, a process or a method consistently performs at a specified level.

6. Master validation plan The Master Validation Plan is a document pertaining to the whole facility that describes which equipment, systems, methods and processes will be validated and when they will be validated. The document should provide the format required for each particular validation document (Installation Qualification, Operational Qualification and Performance Qualification for equipment and systems; Process Validation; Analytical Assay Validation), and indicate what information is to be contained within each document. Some equipment requires only installation and operational qualifications, and various analytical tests need to establish only some performance parameters - this must be explained in the master protocol along with some principles of how to determine

which of the qualifications are required by each, and who will decide what validations will be performed.The Master Validation Plan should also indicate why and when revalidations will be performed, either after changes or relocation of equipment or systems; changes to processes or equipment used for processing; or for changes in assay methods or in

equipment used in tests. If a new process or system is implemented, a Design Qualification (DQ) may be necessary. Guidelines for such cases should be included in the Master Validation Plan. A Design Qualification would be necessary when planning and choosing equipment or systems to ensure that components selected will have adequate capacity to function for the intended purpose, and will adequately serve the operations or functions of another piece of equipment or operation. For example: i) a water system must produce sufficient water of specified quality to serve the requirements of the facility including production, testing, and as a source for steam or for a second system producing higher quality water; ii) a steam generator must produce sufficient steam of the correct quality to fulfill all the autoclaving needs and Steam-in-Place (SIP) cleaning procedures of the facility; or iii) the equipment chosen for a particular operation must have sufficient space and access for proper cleaning operations and maintenance. The order in which each part of the facility is validated must be addressed in the Master Validation Plan. For example the water system should be validated before validating a piece of equipment that uses this water system. The IQ, OQ and PQ must be performed in order: the master validation plan should indicate how to deal with any deviations from these qualifications, and state the time interval permitted between each validation.

6. Change control A qualification/validation study is designed for defined parameters and measures specified outcomes. Any modifications made to equipment, systems, processes or procedures may change the parameters or affect the expected outcomes. Therefore any

change that is made after initial validation is complete must be controlled. Change control must be a formal process following a pre-determined procedure set out in a Quality Assurance document (e.g. a QA SOP or in the Master Validation Plan). The change control procedure should include the planning and submission of a proposal for the change with a rationale and anticipated impact on the function, operation or performance. The proposal should be prepared by the department requesting the change and reviewed and approved by QA, management and other appropriate departments (change control team). The effect of the change on the specific system/process under consideration as well as the wider implication for other systems and processes of the facility. Re-validation of the system/process or other systems may be necessary depending on the significance of the change. No changes should be made for any validated, approved equipment/systems/tests/processes without formal review and approval via the change control procedure.

7. Facility systems and equipment The validation protocols for equipment and systems are normally divided into three segments: Installation Qualification, Operational Qualification and Performance Qualification, abbreviated as IQ, OQ, PQ. For systems and equipment, Performance Qualification is often synonymous with Validation. Depending on the function and operation of some equipment, only IQ/OQ are required. For equipment whose correct operation is a sufficient indicator of its function, and that are monitored and/or calibrated on a regular schedule (e.g. pH meter, incubator, centrifuge, freezer), the installation

and operational qualifications are performed. Systems such as air, water, steam, and major equipment which perform critical support processes, such as sterilization (autoclave, oven), depyrogenation (oven or tunnel), or lyophilization, require installation, operational and performance qualifications.

The following table lists the typical categories of systems and equipment which require performance qualification Systems Equipment Air (HVAC) Autoclave Compressed air Depyrogenation oven or tunnel Pure Steam Lyophilizer Raw steam Continuous flow centrifuge Purified water WFI Central vacuum Each IQ, OQ, and PQ protocol provides the specific procedure to follow, information to be recorded, a set of acceptance criteria, and a list of materials, equipment and documents needed to perform the validation. 7.1 Installation qualification (IQ) This document should be written for the critical processing equipment and systems that are used within the facility, e.g. an HVAC system, an autoclave or a pH meter. The IQ should list all the identification information, the location, utility requirements and any safety features of the equipment. The IQ protocol prepared for each piece of equipment or system lists the name, description, model and identification numbers, the location, utility requirements, connections, and any safety features of the system/equipment which need to be documented. It should verify that the item matches the purchase specifications, and that all

drawings, manuals, spare parts list, vendor address and contact number, and other pertinent documentation are available. 7.2 Operational qualification (OQ) This document outlines the information required to provide evidence that all the components

of a system or of a piece of equipment operate as specified. This involves testing of all normal operation controls, all alarm points, all switches and displays, interacting controls, and any other indications of operations and functions. The OQ document should provide a listing of SOPs (or reference to specific manual instructions) for operation, maintenance and calibration; information on the training of operators; and instructions for any static or dynamic tests to show that the equipment operates as expected under normal conditions. Specifications and acceptance criteria must be defined for all the operations. The OQ document should include information on equipment or system calibration, pre-operational activities, routine operations and their acceptance criteria. 7.3 Performance qualification (PQ) This part of the validation for systems and equipment is performed after both Installation and Operational Qualifications have been completed, reviewed and approved. The PQ document describes the procedure or procedures for demonstrating that a system or piece of equipment can consistently perform and meet required specifications under routine operation and, where appropriate, under worst case situations. The PQ should include a description of the preliminary procedures required, the detailed performance test(s) to be done, and the acceptance criteria for each test. The PQ also requires that other supporting equipment used during the qualification have been validated (e.g. the steam system must be validated before the autoclave can be validated.