SITE MASTER FILE

SITE MASTER FILE

Site Master File that is useful to the regulatory authority in planning and conducting GMP inspections. The Site Master File is prepared by the pharmaceutical manufacturer and should contain specific information about the quality management policies and activities of the site, the production and/or quality control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, a Site Master File need only describe those operations, e.g. analysis, packaging, etc.

When submitted to a regulatory authority, the Site Master File should provide clear information on the manufacturer’s GMP related activities that can be useful in general supervision and in the efficient planning and undertaking of GMP inspections.

A Site Master File should contain adequate information but, as far as possible, not exceed 25-30 pages plus appendices. Simple plans, outline drawings or schematic layouts are preferred instead of narratives. The Site Master File, including appendices, should be readable when printed on A4 paper sheets.

The Site Master File should be a part of documentation belonging to the quality management system of the manufacturer and kept updated accordingly. The Site Master File should have an edition number, the date it becomes effective and the date by which it has to be reviewed. It should be subject to regular review to ensure that it is up to date and representative of current activities.
Each Appendix can have an individual effective date, allowing for independent updating.

TABLE OF CONTENTS

• GENERAL INFORMATION ON THE MANUFACTURER
• Contact information on the manufacturer
• Authorized Pharmaceutical Manufacturing, Activities of the site
• Any other Manufacturing Activity Carried out on the site.
• QUALITY MANAGEMENT
• The quality management system of the manufacturer
• Release Procedure of Finished Products
• Management of suppliers and contractors
• Quality Risk Management (QRM)
• Product Quality Reviews
• PERSONNEL
• PREMISES AND EQUIPMENT
• Premises
• Brief description of Heating, Ventilation and Air Conditioning (HVAC) systems
• Brief Description of Water System
• Brief Description of Other Relevant Utilities, such as steam, compressed air, nitrogen, etc.
• Equipment
• List of Major Production and Control Laboratory Equipment’s
• Cleaning and Sanitation
• Good manufacturing practices critical computerized systems
• DOCUMENTATION
• PRODUCTION
• Types of Products
• Process Validation
• Materials Management and Warehousing
• QUALITY CONTROL
• DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS
• Arrangements and Recording system for distribution
• Arrangements for handling of complaint and product recalls
• SELF INSPECTIONS
• REFERENCE
• REVISION HISTORY

General Information on the Manufacturer /Contact Information on the manufacturer

NAME AND OFFICIAL ADDRESS/NAME AND STREET ADDRESS OF THE SITE:

Name of the Factory / Address /24 hours contract Tel. No./E-Mail/Head office & Address, / CONTACT INFORMATION OF THE SITE (NAME AND ADDRESS): 

The facility is located at ________________________________________________ INDIA, which has an abundant Green Environment, free from pollution and has good quality of water. The location is well connected by rail, road and air transport. The plant is surrounding area of site is having garden with plantation and forest. There are no units nearby which generate smoke or hazardous waste. company was established in the year __________, commercial production to be start in ____________________at _____________________(India), our facility approved by WHO- GMP.

The Plant is designed to manufacture tablets, capsule, dry syrup, Large Volume Parenteral and Small Volume Parenteral products.

AUTHORIZED PHARMACEUTICAL MANUFACTURING ACTIVITIES OF THE SITE: The World Health Origination (WHO), Good manufacturing practice (GMP) and cGMP (Current good manufacturing practice) to manufacture the pharmaceuticals products have accredited the site.

The premise is licensed for the manufactures of Pharmaceutical Product vide Mfg. License Nos. ___________________________ valid up to _________________ for the manufacturing and sale of drugs-

Valid Manufacturing Authorization -Annexure – I.

M/s. _____________________________________ is an independent State- of- the- art -manufacturing facilities of international standards, which include ultra-modern plant, machineries. Latest manufacturing equipment, Quality control instruments. Its operation spreads globally with its strong international distribution background and marketing credentials for widest dosage form bandwidth and both Small Volume parenteral and Large Volume parenteral.

TYPE OF PRODUCTS CURRENTLY MANUFACTURED ON-SITE:

• Small Volume parenteral in glass, Respule & Ophthalmic.
• Large Volume parenteral in glass & Plastic bottles.
• Tablets/Capsules/dry syrup

List of products manufactured at the site – Annexure-2

List of GMP& WHO GMP Certificate Manufactured: – Annexure-3

ANY OTHER MANUFACTURING ACTIVITY CARRIED OUT ON THE SITE: Only pharmaceutical dosage forms are   manufactured at this site.

QUALITY MANAGEMENT:

The Quality management system of manufacturer: The Company has undertaken to work under the guidance of Pharmaceutical Quality Management (PQM) “To create customer and to retain customer within organization and outside organization” by fulfilling customer’s needs, expectation and satisfaction by acting on it. Organization leadership having vision, direction, shared values by setting challenging targets and goals and implementation of same through involvement of people at all levels by using knowledge, experience and through training. A process and system approach based system results into organization’s effectiveness and efficiency by continuous improvements and up gradation. Decisions and actions are based on the analysis of data and information by using suitable management’s tools and technology.

Company Quality Policy: Our Quality policy is based on cGMP guidelines, laws and regulations governing the manufacture of pharmaceutical products.

Our Quality Policy is committed to produce developing unsurpassed levels of drug formulation with highest quality, safety and efficacy for customer satisfaction.

Our Quality Policy Comprises of – It strives for total customer satisfaction in all its processes through continual improvement, training and employee motivation.

Treating health, safety and environmental protection as an integral part of our quality strategy.

“We shall create an environment where each employee contributes to all aspects of our business processes. We shall strive for continuous improvement to meet with customer satisfaction.”

Implementation of quality policy is done through Quality system based on current good manufacturing practices in conformance with national and international regulatory standards. 

Manufacture & supply of consistent quality drugs, which consistently meet customer and regulatory requirements.

Internal customer focus and beneficial relationship with supplier and customers.

Adopting measures for prevention of pollution by monitoring and control of air, water and land contamination such as emission and waste generation

Effective utilization of natural resources.

Improving health and safety performance within the organization.

Continual improvement of quality, environment health and safety management, system based national and international standards.

Complying with applicable environmental. Health and safety legislation and regulations.

Involving all employees in improvement and innovation in all spheres of management.

Generating awareness amongst all concerned for their roles and responsibility in ensuring good quality, environment health and safety management system.

This is achieved through the Quality principles laid down in the manual and relevant operating procedures to ensure that each product meets the customer’s requirement for safety, efficacy & quality. These QUALITY principles are used in the planning, designing, construction, testing of quality systems & qualification of facilities.

The Engineering/Maintenance, Materials Management, Vendor development, Production, Quality Assurance & Quality Control departments are all required to comply with these Quality principles.

QUALITY is   mandated and supported by top management and coordinated by Quality Assurance, which is responsibility of everyone in the plant. The effectiveness & applicability of Quality Assurance system is regularly monitored.

ELEMENTS OF QUALITY ASSURANCE SYSTEM: The Quality Assurance Department has responsibility and authority to define norms and regulations for various activities including Personnel Training, Sanitization and cleaning of general areas. Quality Assurance Department reviews the production records to ensure that all the manufacturing operations are carried out as per the laid down instructions.

Quality Assurance Department ensures that all production facilities are provided to meet cGMP requirements and have adequately trained and qualified persons, for carried out the operations. All manufactured operations are clearly defined and checked routinely to confirm the quality of products.

RESPONSIBILITY OF QUALITY ASSURANCE FUNCTIONS: Has authority and responsibility of assessing and ensuring that all the products manufactured at site as per regulatory requirement.

To monitor the entire manufacturing and quality control activities and to notify the management of any significant variation from the company standards which potentially affect the product quality.

To ensure for each product there is an annual product quality review covering manufacturing activities, in order to provide assurance that product confirms to customers and regulatory requirements.

To establish that manufacturing activities including any proposed changes are in accordance with regulatory requirement.

Any changes which affect compliance with product standard should be approved by Head Quality Assurance before they are implemented.

Responsible for ensure the compliance of cGMP practices at all stages of production and control.

Review of master documents and its control.

Review of production records and in process controls.

Review of product specifications and test procedures.

Responsible for Release/Reject of Finished Goods.

Quality audits and quality manual.

Review of Stability studies.

Vendor Qualifications.

Training program.

Deviation and failure investigation.

Change control management.

Product complaints and recall.

Validations and Qualifications.

Calibration program.

Returned goods and their disposal.

Monitoring of Plant preventive maintenance.

VENDOR APPROVAL: Vendors of all active ingredient as well as Excipients and packaging materials are assessed as per approved procedure and on the basis of the satisfactory assessment, the vendor is approved prior to purchase of the material. Critical suppliers shall be assessed as per the requirements of the company, with respect to quality. Assessment of suppliers of critical raw materials and packing materials is achieved through regular audits of the Vendors/ Traders & follow-up audits or through review of Satisfactory Vendor assessment questionnaires.

AUDIT PROGRAM: A detailed procedure and schedule of Self-Inspection /Internal Audit program is in place and implemented.

The program of Self-Inspection /Internal Audit is developed and updated regularly to ensure that there is a systematic examination of the Quality Management Systems within the organization schedule on the basis of the importance of the activity.

All Self-Inspection /Internal Audit are performed by trained and knowledgeable staff.

Self-Inspection /Internal Audit are conducted against relevant current Good Manufacturing Practices and Regulatory requirements.

The deficiencies discovered are reported to top management level to ensure that adequate follow up and timely, effective action is taken.

Self-Inspection /Internal Audit Procedure includes documented follow up and completion of audit recommendations.

DOCUMENT CONTROL: The company has a documentation system which ensures that the correct version of all necessary documents is available to the users and that such documents are approved before use and that any amendments to them are properly authorized.

RELEASE OF FINISH PRODUCT: Product release is done by the Qualified Person of Quality Assurance after review of all manufacturing (Batch Manufacturing Records) and certificate of analysis of finished product.

RELEASE PROCEDURE OF FINISH PRODUCTS: As soon as the batch is packed, Quality Assurance personnel draw samples as per the SOP for testing of Finished Products. These samples are tested by Quality Control Department against the approved specification and testing procedure. If the samples conform to the specifications, then the batch is approved through Certificate of Analysis (COA). Quality Assurance Department checks the COA and reviews the Batch Records for completeness of documents. Quality Head or his designee from QA reviews the batch records for completeness of documents. Quality Head or his designee from QA then releases the Batch for sale and distribution.

MANAGEMENT OF SUPPLIERS AND CONTRACTORS: The cGMP guidelines and Customer audits are used by the company to assess the quality system within the company and for the assessment of suppliers; the company maintains its own vendor audit and appraisal system for evaluation of Vendors.

VENDOR APPROVAL: A complete vendor approval plan takes care of Suppliers of critical starting materials and packing materials which are assessed by routine Audits / by questionnaires.

USE OF OUTSIDE TECHNICAL ASSISTANCE: The site uses outside analytical service for verification of results where there may be disagreement with suppliers or other third parties or for a specialized analysis.

Name and address of the Laboratory: [Annexure-4]

QUALITY RISK MANAGEMENT: Quality risk management includes systematic processes design to coordinate, facilitate and improve   science-based decision making with respect to risk. Possible steps used to initiate and plan a quality risk management process includes the following:

Define the problem and/or risk question, including pertinent assumptions identifying the potential for risk;

Assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk assessment;

Identify a leader and necessary resources;

Specify a timeline, deliverables and appropriate level of decision making for the risk management process.

PRODUCT QUALITY REVIEW: The efficacy, safety and quality of the product is assured through a series of validations carried out upon manufacture and analysis. Each production batch is reviewed by QA for completeness of starting material, manufacturing, analysis, Packing, IPQA, Yields, deviations, environments, out of Specification (OOS), controlled changes etc. prior to the release of the batch. Product Quality Review is reviewed annually for all products with more than 3 batches manufactured in a calendar year.

PERSONNEL:

Organizational chart :Attached [Annexure-5]

Qualification, experience and responsibility of key personnel related to production and

quality is described under Annexure – 5.

Number of employees engaged in production, quality assurance, quality control, engineering, storage and distribution on the site – Attached [Annexure-5]

Outline and Arrangement of Basic and In-Service Training and Records Maintained.

Identification of training needs: Training needs of employee are identified by qualification, past experience, personal discussion, and on the basis of day-to-day observation by respective department head, with respect to their job responsibility. On the basis of these identified training needs, a complete training program is planned.

For all new recruitment, a set of training for each department is defined.

cGMP training are conducted for both staff and workman on following subject:

Workmen are given the following training at the time of their employment.

The ideal working environment in the pharmaceutical industry.

Hygiene and sanitation.

On-the-job training on shop floor.

Safety during working.

General discipline and work conduct.

Management staff personnel are given an induction in different departments at plant at the time of joining. Job orientated training is given by Departmental Heads.

Examples of In-house trainings are as follows –

cGMP Training

Behavioural Training

Safety Training

Experts in various subjects conduct the above training sessions. Skill development training is given on the job at the work site in the classroom. Motivational training is provided in the classroom by external or internal facility.

Evaluation of effectiveness of training: Effectiveness of training is evaluated by feedback form and by conducting test / discussion. Retraining needs are identified by personal discussion with the employee and on the basis of day-to-day observation by respective department head

Brief details of training records

Various records maintained for training are-

• Identification of training needs.
• Training calendar
• Training material.
• Training attendance
• Evaluation form

Routine medical check-up: Routine medical check-up is scheduled before joining of every employee or as a when required. Sickness or contact with sick person must be reported to the HR department before resuming the work.

Clothing: Special clothing is designed, which suits the production requirement and comfort of workman. Clothing is made of lint free cloth.

Clothing instructions: A standard operating procedure is provided in the change rooms, which specify what to wear, when to wear and how to wear. Photographs also provided in the change room. Regular training session is also conducted for gowning and over gowning.

All employees are advised and encouraged to observe the following guidelines: –

1. To wash hands properly.
2. To keep hair short and clean at all times. Combing of hair is strictly prohibited in GMP areas.
3. To keep the nails well-trimmed and cleaned.
4. Not to eat or drink in manufacturing area and laboratory.
5. To follow standard gowning procedure to enter into production area

PREMISES AND EQUIPMENT:

PREMISES: Total built area is _____________ sq. feet.  Details of area of plant areas.

The premises have been designed keeping cGMP, Safety and Manufacturing Capacity in consideration. Premises and equipment’s are located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design is in such a way that it is aimed to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination and any adverse effect on the quality of products. The facility for manufacturing of Parenteral is having separate section for each activity as follows:

Store Area: Separate stores for raw material with segregation for Quarantine, Approved and controlled temperature, Dispensing, rejected materials, LDPE granules, packing materials and printed packing materials.

Servicing Area: For materials feeding to classified area.

Manufacturing: The activities carried out are solution preparation; separately for LVP& SVP Grade B and C.

Mixing Room: The activities carried out are solution preparation and filtration; Separately for LVP & SVP area, Grade B and C.

Filling Room: Equipped with pre-qualified (separately for LVP & SVP) under Grade A.

Sterilization Area: Having pre-qualified automatically controlled Autoclave for sterilization of    filled/sealed bottles and vials/ampoules terminal sterilization.

Visual Inspection and Packing Area: The activities carried out include visual Inspection of 100 % quantity of batches with trained and qualified visual inspectors, labeling and packaging of Finished Product.

Quarantine Area: To store finished goods until their Release by QC in separately identified   area for LVP and SVP.

Finished goods storage area: To store released finished goods ready for dispatch.

Nature of Construction and Finishes: The building is a Reinforced Cement Concrete (RCC) frame structure in concrete with clean room partitions.

Flooring: Two types of flooring have been done.

Kota flooring: Kota is a naturally available stone in India having very high abrasion strength & Kota jointing is done by epoxy and once polished gives very smooth surface finish, dust-free, easy to clean floor.

Epoxy Flooring: The core production areas have continuous epoxy flooring with a smooth finish, which is chemical/microbial resistant and dust-free.

All areas of the corners are rounded and a coat of impervious material applied to the walls.

Painting: Three types of painting have been done.

Acrylic Emulsion, which is, used in entrances, toilets and change rooms areas. Epoxy paint, all cores processing area paint is applied with epoxy paint.

Epoxy paint is applied which is characterized by excellent chemical, oil, water resistant, smooth finish and excellent Algae and Fungal growth resistant.

External paint is cement based water repellent paint.

Door & Windows: All doors are of Anodized Aluminum having flush glazed view panels.

BRIEF DESCRIPTION OF HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS: To avoid cross contamination and to maintain relative humidity, temperature and Pressure Difference of the manufacturing areas with Air handling Units, total of __________­­­­­Air handling Units for sterile facility., Provided in the manufacturing, warehouse, quality control and microbiology section. Temperature and humidity are controlled and maintained within the limits as per the requirement of product.

The pre-filters are cleaned as per the frequency described in the SOP for cleaning of the filters.

In case of pressure differential failure, all the production activities are stopped, and the filters are replaced with cleaned filters.

Validation of air handling unit is done through the studies of parameters like air velocity, air change per hour, temperature, relative humidity, non-viable particle count, HEPA filter integrity, pressure differential across HEPA filter, Air flow visualization, recovery test, viable particle count, except recovery study similar studies are done for RLAFs (Dispensing and sampling booths). In processing area daily monitoring of differential pressure, temperature and relative humidity. Microbial monitoring is being done in critical processing manufacturing area on daily basis and Monthly for non-critical area, and daily in microbiological section.

Air changes are at least 20-40 per hour in ISO-8 (100,000) classified area, of ISO-7 (10,000) that is 40-60, ISO-6 (1000 surrounding LAF) air changes is 60 – 80 and in ISO-5(100 under LAF) that is 72 to 108 FPM. Critical manufacturing area having a positive differential relative to adjacent less clean areas to avoid cross contamination. The return air is passed through return air riser and 90% of it is again re-circulated with intake of 10% fresh air every cycle. The return air risers are located in critical process areas. Filters are arranged in the series of 10m (return air filter), 10m (pre-filter), 3µ (fine filter) and 0.3m (HEPA filter) for critical areas and for non-critical areas filters are put in the series of 10µ and 3µ arrangements.

All the areas are provided with appropriate ventilation system to maintain the required room conditions with respect to temperature, relative humidity, non-viable particulate counts and Pressure differentials. The critical area for manufacturing of sterile products meets Grade – A requirements with background of Grade – B/C.

For FFS machine, filling takes place under controlled area (Grade – A) of filling hood and FFS machine surrounded by Grade – C area.

For glass vial filling, filling takes place under LAF (Grade – A) that is surrounded by Grade – B area.

Pressure differentials are maintained as per the defined procedures. Relative humidity in the different sections is as mentioned below. 

Limit For Temperature/Relative Humidity: For all area:  NMT 25°C & NMT 60 %

Note: If limit for temperature & RH is specified in BMR/BPR/any documents, in that case follow the same limit as specified in respective documents and limit mention in this SOP.

The ventilation system design is based on re circulation of air. 80 – 85% of the air is re-circulated and 15-20 % fresh air is taken in.

Air changes in the Grade – B area is Not Less Than 60/Hr., Grade – C Not Less Than 40/Hr. and for Grade – D area Not Less Than 20/Hr.

Total ___________Numbers of HVAC catering ground and first floor at manufacturing site.

Filter Replacement Policy: All ventilation filters are changed or claimed for maintenance, based on the pressure drop cross filters from the design range.

All HEPA filters are checked for integrity using a challenge aerosol at the upstream of the filters and the filters are scanned downstream using a calibrated photometer. 

Revalidation: Revalidation of the AHU system is carried out as per given frequency or earlier if any changes are incorporated in the system or in the facility.

1. Particulate matter count: Once in six months.
2. Filter integrity testing : Once in Six months.
3. Air changes calculation: Once in six months.
4. Air pressure: Daily
5. Temperature and Humidity: Daily
6. Microbiological monitoring by settle plate method and by Swab method: daily
7. Recovery Test: Once in Year.

BRIEF DESCRIPTION OF WATER SYSTEM:

Source of Raw water: There is one Bore wells as a source of raw water & stored in underground storage tank. Water system is designed with reference to WHO GMP prevalent industry standards.

Purified water: Generation, Storage and Distribution of purified water as per Respective SOP. The source water is bore well. Purified water is generated from chlorinated water followed by multigrade and then by Soft water plant followed by RO-EDI treatment and collected in a sanitary storage tank having the capacity of 5000 Liters.Online monitoring conductivity sensor provided for monitoring of conductivity with auto rejection mechanism.PW storage tank (5000 liter) and distribution loops are made of Stainless Steel 316 L electro polished internal surface with sanitary grade fittings and valves.Pipes are electro polished to < 0.5 Ra with zero dead legs and slope NLT 1/100. To meet anticipated maximum coincidental demands and to ensure turbulent flow around the Purified water loop during these instances, the loop has been specified for a velocity in a range NLT 1.2 m/second with a minimum velocity in the return loop at 1.2 m/s.PW is distributed through main distribution loop to individual user points. Purified water meets the specified limits as per current IP/BP/USP. Purified water is use for equipment primary cleaning, intermediate washing of primary containers (LVP and SVP).

Pre-treatment system consists of Bore well → Sodium Hypochlorite dosing (NaOCl) dosing→ Raw water Storage tank (50KL) → Soft water Plant → Self Cleaning Disk Filter (SDF)→ SMBS→ Antiscalent dosing→ pH correction → 5 Micron Cartage Filter (5µ) →RO-I Feed High pressure pump→double membrane housing CSRO→RO-II Feed High pressure pump→ HSRO Membrane→EDI→UV→ 5.0KL Purified Storage Tank .

Potable water is generated by chlorine treatment, Multi grade filtration and used for soft water generation from RO-I water.

Soft water is generated by water passing through softener. It is stored in a SS 316L tank with __________Liters capacity.

Appendix-7: P&I Diagram for PW generation & distribution system.

Water for Injection & Pure Steam Generation: Purified water is used as a feed for generation of WFI and pure steam. Purified water is fed into Multi column distillation plant (1000 L/hr.) for generation of water for injection and pure steam generator (500 kg/hr) for generation of pure steam.Generation, Storage and Distribution of WFI shall be done as per SOP and operation and cleaning of pure steam generation system as per SOP. The WFI and Pure steam quality shall meet the specifications as per current IP/BP/USP.

Water for injection Distribution: WFI distribution system is provided with storage tank (5000 liter). Distribution loops are made of Stainless steel 316L with sanitary grade fittings and valves. Pipe is electro polished to < 0.5 Ra with zero dead legs and slope NLT 1/100. To meet anticipated maximum coincidental demands and to ensure turbulent flow around the Purified water loop during these instances, the loop has been specified for a velocity in a range NLT 1.2 m/sec and with a minimum velocity in the return loop at 1.2 m/s. and minimum pressure of 1.5 Kg/ cm². WFI is circulated at NLT 80°C to inhibit the microbial growth.

Sanitization: Sanitization of RO-EDI system as per SOP. Purified water storage and distribution system is sanitized by Hot water and WFI storage and distribution by pure steam as per SOP. A detailed SOP describing sanitization procedure of PW and WFI Distribution Loops is available as per SOP. WFI is use for manufacturing and equipment final cleaning, final washing of primary containers whereas pure steam generation and distribution is used form sanitization of WFI as per SOP. Pure steam generation and distribution shall be clean as per SOP.

Refer Annexure – VII for Schematic diagram for Water Generation, Storage and Distribution system

The sampling of different grades of water is carried out from the designated Point of Use/Sampling points for chemical and microbiological testing as per the well-defined Standard Operating procedure.

Online TOC analyzer was installed in Purified water and WFI return loop for monitoring TOC level in Purified water and Water for injections.

The Purified water distribution system is sanitized by hot water at 80°Cwith exposure time of 60 minutes. Water for injection distribution system is sanitized by pure steam at 121°C with exposure time of 60 minutes.

BRIEF DESCRIPTION OF OTHER RELEVANT UTILITIES, SUCH AS STEAM, COMPRESSED AIR, NITROGEN, ETC. DESCRIPTION OFDESCRIPTION OF OTHER RELEVANT UTILITIES: Other Utilities consisting compressed air plant having capacity of 214 CFM, Nitrogen Generation plant having capacity 12 Nm³ and effluent treatment plant.

EQUIPMENT: All the production equipments are designed to meet cGMP requirements. All contact parts of the equipment are constructed of Stainless Steel 316 grade.

Equipment’s are qualified for their Design (DQ), Installation (IQ), Factory Acceptance Test (FAT), Operational (OQ) and Performance (PQ). All equipments are placed to suit the operations to be carried out. The layout and design of equipment is aimed to minimize the risk of errors and permit cleaning and maintenance in order to avoid cross contamination or any adverse effect on the quality of products produced.  Analytical Balances and other measuring equipment are of an appropriate range to achieve accuracy and precision.

QUALITY CONTROL: Quality Control Laboratory is equipped with sophisticated equipments/instruments like UV Spectrophotometer, FTIR, HPLC, Polarimeter, Analytical Balance, pH meter and Conductivity Meter, BOD incubators, Karl Fischer Titrator, Melting Point Apparatus etc. All the chromatographic instruments are supported by suitable validated software. Quality Control is equipped with other general quality control equipments like melting point apparatus, etc. All sophisticated analytical instruments are validated and routinely calibrated.

The microbiology laboratory is facilitated with separate facility for determining the microbiological purity of water, raw material and finished products.

Computers are used for documentation purpose and data entry at different departments. Access to department computers is restricted by using suitable passwords. List of equipment:  Production and Quality Control [Annexure-8]

Maintenance (Description of planned preventive maintenance Programmed and recording system)

Regular preventive maintenance is undertaken in all the manufacturing areas for various equipment/facilities as per written procedures and records are maintained thereof. All details Including maintenance schedules, records of services or breakdown and any modifications are recorded.

Engineering department is responsible for maintenance and servicing of the machinery. Engineering personnel have a scheduled preventive maintenance program for all production machinery and utilities. Some Quality Control equipments are under Annual Maintenance contracts. Agreements are drawn and the records are maintained. Service engineers visit during the year at prescribed frequencies for the equipments that are under the Annual Maintenance Contract.

Maintenance routine checkups, which could affect the product quality, are clearly identified. If any major changes are made for equipment, then the equipment is revalidated.

Qualification and Calibration, including the recording systems and arrangements for computerized system validation.

All equipments are qualified (URS, FAT, SAT, DQ, IQ, OQ and PQ) before use. Records of validation, which are maintained in prescribed formats, are reviewed periodically. A Validation Master Plan (VMP) is designed for validation of facility, utilities, process and cleaning operations. The validation plan is designed to demonstrate that the quality features are built into the facility, utilities and processes ensuring that they are fully functional, remain in place and conform to the relevant regulatory requirements. Equipment re-validation is carried out if there is any change(s) or after major breakdown in the major component that could have a considerable impact on the performance of the equipment. Additionally, all the critical equipments are subjected to routine re-validation.

All validation activities are performed in accordance with the approved protocols.

Equipment calibration: All the equipments and instruments are calibrated as per the calibration planner before use as per the procedures and frequency mentioned in the respective SOPs. All the calibrated equipments have the calibration tags mentioning the calibration status and details of equipment. All the equipments are calibrated either in-house or by pre-approved external agencies with standards traceable to some national agencies.

CLEANING AND SANITATION: The manufacturing premises is cleaned and maintained in an orderly manner and there is no chance to accumulate waste, Dust and debris are disposed in timely and sanitary manner. SOPs are available describing responsibility, cleaning procedures and sanitization procedure/ methods / specifications, cleaning agents used and schedule. Rodenticide and insecticides are used to keep rodent, insect and other pests under control.

Written SOPs are available for cleaning of equipment, vessels, etc. Records of cleaning are maintained. Adequate measures are taken to ensure that clean equipment; vessels are not contaminated prior to use.

Disinfectants are rotated / changed as per the schedule mentioned in the SOP. Equipment cleaning validation studies are used for evaluation of effectiveness of cleaning procedures. Equipment’s are subjected to swab / rinse tests for chemical analysis / plate exposure methods for microbial counts.

Cleaning of water supply systems including storage tanks is done as per written procedures. Pre-filters and fine filters of air handling system are cleaned at defined frequency or schedule.

The pest control activities like use of insecticides etc. is outsourced to external agency specialized with handling of these substances. These activities are done and recorded as per written procedures mentioned in the SOP and only substances approved for use in pharmaceutical industry is used. Insect /rodent traps are also placed at suitable points to control the insect/rodent infestation in the area.

GMP CRITICAL COMPUTERIZED SYSTEM: Computer is utilized for Material Management and Inventory system. Microprocessor (PLC) is utilized in the Automation of many productions machine.

DOCUMENTATION:

Arrangements for the preparation, revision and distribution of necessary documents. Well-established documentation system exists to implement Good Documentation Practices, which is a part of Quality Assurance. Clearly written documents are prepared, reviewed and controlled, which prevents the errors from verbal communication and permits traceability for all activities carried out. Quality Assurance is responsible for the revision and distribution of documents and concerned departments are responsible for preparation and initiation of changes in procedure. Master documents are stored in the archives of Quality Assurance department and controlled copies are distributed to the concerned departments.

The documents are designed, prepared, reviewed and controlled as per the SOP(s).

Documents are approved and authorized, signed and dated by the designated persons.

The documents specify the title and nature, also mention the purpose, they are laid in an orderly fashion. Reproduced documents are clear and legible and are appropriately stamped. These are normally reviewed as per the review period mentioned in the relevant SOPs.

An SOP is available for correction of a wrong entry in a record.

The batch production and control records are completed at the time of each operation in such a way that all significant activities concerning the manufacture of the product are traceable.

Batch records are retained for one years after the date of expiry of the relevant drug product. SOP is available for issuance, traceability during storage, retrieval and destruction of records.

Any change in the approved documents is processed through a system of Change Control.

Different types of master documents and records available with company are listed below:

Site Master File, Master formula Record, Process Validation, Batch Manufacturing Records, Validation Master Plan, Validation Protocols and Reports, Stability Protocol and Reports, Standard Operation Procedures, Specifications (Raw Material, In-process Material and Finished Product), Standard Test Procedures and Analytical Method Validation.

Documentation Cell of Quality Assurance department controls all the documents. The system is designed to ensure that all the documents are properly distributed, controlled and stored so as to maintain their integrity. The access to stored documents is limited to the authorized persons only and all documents are stored in such as way so that they are easily retrievable.

Any other Documentation Related to Product Quality which is not mentioned elsewhere

Other related documents are also available. These are:

• Annual Product Reviews
• Internal Audit Reports
• Calibration Records of instruments
• CAPA (Corrective and Preventive Actions)
• Change Controls/ Deviations Records
• Cleaning and sanitization records
• Disposal Procedures and their Handling
• Induction Manual
• Investigation Reports for Product Complaints
• Non-Conformance Reports (NCRs)
• Qualification documents like URS, DQ, IQ, OQ and PQ of Equipment’s/ Instruments.
• Vendor Approval records
• Sampling Procedures
• Training Evaluation Records
• User Requirement Specifications (URS)
• Reports of water samples and other routine microbiological testing
• Safety Manual

PRODUCTION: Types of Products:

Sterile Products: Small Volume and Large Volume

All manufacturing and packaging operations are carried out in controlled environmental conditions. The operating procedures are specified in the SOPs. The details of manufacturing and packaging operations are recorded and maintained in controlled Batch manufacturing Records (BMR).

All manufacturing operations and controls are carried out under the supervision of competent technical staff. Dedicated areas have been allocated for storage of material appropriate to their status.

All compounding and storage containers, major equipment used in production of a batch are conspicuously identified and labeled with color-coded labels mentioning the name of product, batch no., batch size, quantity issued and stage of manufacture. Each label is signed and dated by a manufacturing chemist and is counter checked by in-process Quality Assurance chemist.

Prior to manufacture, raw materials are sampled and analyzed by QC department. Only approved materials from QC are used for manufacturing and approved bulk in-process materials are taken for packing operations. Finally, samples of finished goods are subjected for analysis as per requirement. Head- QA/ or his/her designee, reviews the documents of the approved finished goods prior to release of each batch of each product for sale and distribution.

PROCESS VALIDATION: Process validation is action taken to demonstrate, and to provide documented evidence that a process shall, with a high degree of assurance, consistently achieve the desired and intended results. Before process validation, the term equipment qualification is an essential as a pre-validation phase. In addition to such considerations as equipment specification, equipment design and equipment purchase, requires attention to equipment qualification. The validation policy of the company is to keep its manufacturing facility with utilities, critical equipments, manufacturing processes, cleaning and disinfection procedures and analytical methods in a validated state so as to produce drug products of consistent quality, as per cGMP norms, with high degree of confidence with established documented evidence.

Process validation of all critical operations is carried out with respect to VMP. The Validation protocols are prepared by validation team, which is further approved by respective functional heads. These protocols are followed for execution of validation activity. Also, routine trend analysis is performed for products. Following types of validations are carried out for the processes:

Prospective Validation: During product development, the production process is broken down into individual steps. Each step is evaluated to determine the critical factors/parameters that may affect the quality of the finished product. A series of experiments are planned and documented fully. A protocol based prospective validation includes the following elements:

• Description of the process
• Details of the equipment / facilities to be used
• Identification of Critical Steps
• Description of the validation plan- Sampling program/ plan, test plan
• The acceptance limits and the time schedule.
• Details of methods for recording and evaluating results, including statistical analysis.
• Conclusions and recommendations.

Concurrent Validation: Concurrent validation is also carried out on the processes, which are better understood, to establish documented evidence that a facility and process do what is supposed to do, based on the generated evidence during actual implementation of the process.

MATERIAL MANAGEMENT AND WAREHOUSING:

Arrangements for the handling of starting material, packing material bulk and finished products including sampling, quarantine, release and storage: The handling of products are properly planned, controlled and documented for testing of incoming, in-process and final product. Analytical methods are validated. Containers are sampled and tested for identity. Quality Control department is responsible for release of starting materials, packaging materials, in-process and finished products. SOPs are laid down for handling of materials starting from receipt, checking (quarantine) sampling, storage, release, storage of approved materials in segregated areas with proper labeling.

The identification and analysis of materials are confirmed to be in accordance with company’s specifications. All in-process and final tests are planned and specified. Documented tests and inspection procedures are maintained for checking each quality characteristics.

Handling of In-process and Finished Material: Any deviation from the set process is considered a process deviation that is duly recorded and approved by quality assurance. Evaluation and corrective actions taken are also mentioned.

There are SOPs describing sampling of in-process and finished products. In-process Quality Assurance performs sampling.

In-process material and finished products are stored in the designated In-process and finished product Quarantine Areas during the manufacturing process.

To prevent contamination or mix-up risks arising from left over (product, materials and labels) from previous batch, Line Clearance is given by Quality Assurance personnel before any operation begins. This is to ensure that the work area, line and equipment are clean and clear from previous product residues, packing materials or label.

Quarantine, release and storage of finished product: Production quarantines the product until clearance from Quality Assurance department. Final inspection and testing are carried out to ensure that the finished product is complying with all the specified requirements as per approved documents and procedure. Quality Assurance department reviews the completed batch records and Head; Quality Assurance is authorized to release the product after ensuring that all the test results are obtained and batch is approved by Quality Control. Until the product is released, the product is stored in such a way as to maintain the physical and chemical attributes of the product. 

Arrangements for the Handling of Rejected materials and products: Rejected materials are kept in an isolated area dully labeled ‘Rejected’ and are be stored in rejected area assigned for the same.

The rejection reports are issued to the Stores by Quality Control, and these materials are then shifted from quarantine to rejected area. Rejected printed packaging material are either destroyed or defaced prior to the return to the supplier. Online rejections for packaging materials are taken up after generating the online rejection note duly signed by Production, QA and Stores personnel. All destruction activity is done in the presence of Quality Assurance and Quality Control personnel as per procedure mentioned in the SOP.

QUALITY CONTROL: Description of the Quality Control system and of the activities of the Quality Control department. Procedures for the release of finished products The Quality Control department is responsible for testing and assessing the quality of incoming materials, semi-finished products and finished product using approved specifications and for assigning an appropriate status to the products before they are processed further with the great precautions.

To perform all the testing, Quality Control department is equipped with sophisticated equipments. Quality Control department comprises of chemical laboratory, instrumentation laboratory and microbiological laboratory. Raw materials, Packaging materials, In-process materials and finished products are tested as per approved specifications and testing procedures (Pharmacopoeia or In-house). Quality Control department also carries out analysis of various packaging components like Aluminum ploy film, cartons, labels and shippers etc. Microbiological analysis of the BET, MLT or sterility test is done by microbiological section of Quality Control department.

Quality Control department is also responsible for carrying out the post-production stability testing of manufactured batches as per approved protocols that comply with ICH guidelines.

CONTRACT MANUFACTURING AND ANALYSIS: Description of the way in which the GMP compliance of the contract acceptor is assessed Loan License Manufacturing, are, shall be carried out on the contract giver after written agreement between contract giver and contract acceptor with clearly established duties of each party. Loan License Manufacturing is carried out to ensure production quality.

DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS: Arrangements and recording system for distribution Finished products after release for sale and distribution are sent to Finished Product Warehouse, for further distribution. The finished goods are stored and maintained under controlled conditions of temperature and humidity. Materials are segregated, identified, stacked on pallets or racks with appropriate labels

Prior to dispatch, warehouse personnel ensure that the finished goods are approved and released by Head, Quality Assurance. Packed goods are transported to distributors/ customers through contract carriers / courier service. All the records of distribution are maintained, so that complete traceability of each batch of each product is available.

Arrangements for the handling of complaints and product recalls: Quality Assurance is responsible for handling of all product complaint. An SOP is available for the handling of Complaints and Product Recall.

If product is to be recalled from the market, then Head, Quality Assurance acts as product recall coordinator for coordinating all recall activities. The product recall is done as per written procedures, which describes the sequence of actions.

An approved procedure describing retrieval of distribution and sales data, notification to customers, receipt / segregation, inspection of recalled product, investigation and corrective actions are prepared. Based on the nature of the recall the wholesaler / distributors / retailers / medical practitioners are involved in the recall of the product. The recall coordinator informs about the recall to the competent authority.

SELF INSPECTION: Self-inspection (Internal Audits) are planned and carried out to monitor the implementation and compliance with cGMP. Self-inspection is carried as per the SOP of Internal audit and Self-inspection.

Internal audit is either conducted by the internal audit team or by authorized QA personnel. Internal auditors who are part of the internal audit team are selected from various departments except the audited department. All inspections are recorded and compiled as a

Report includes deficiency, proposed corrective actions and persons responsible for taking actions and compliance date.The report is sent to heads of concerned departments. Follow up the action is taken as per compliance dates to ensure that the corrective action is implemented.

LIST OF ANNEXURES

• Annexure-1: Copy of valid manufacturing authorization.
• Annexure-2: List of products manufactured at site.
• Annexure-3: Copy of valid GMP Certificate
• Annexure-4: List of contract testing laboratories.
• Annexure-5: Organizational charts.
• Annexure-6: Layouts of production areas including material and personnel flows, general flowcharts of manufacturing processes of each product type (dosage form)
• Annexure-7: Schematic drawings of water systems
• Annexure-8: List of major production and laboratory equipment

QUALITY MANUAL