ASEAN CURRENT GOOD MANUFACTURING PRACTICE (cGMP)
13 Modules of ASEAN cGMP:
1. Quality Management System
2. Personnel
3. Premises
4. Equipment
5. Sanitation and Hygiene
6. Production
7. Internal Audit
8. Quality Control
9. Documentation
10. Storage
11. Contract Manufacturing
12. Product Complaints
13. Product Recall
Module 1: Quality Management System
GOOD MANUFACURING PRACTICES
All manufacturing process are clearly defined and systematically reviewed.
All necessary facilities/resources for GMP should be provided:
adequate, qualified and well-trained personnel
suitable premises and sufficient space
suitable location
good personal hygiene and proper sanitation
suitable equipment and services
clearly defined manufacturing processes
using unambiguous language
good documentation system
appropriate storage and transport
systematic internal quality audit
proper product recall system
right handling of complaints
comprehensive corrective and preventive action
The Working Instruction should describe step by step instruction specific to a process and machine, specifying the tools, workmanship criteria, tolerance, and direction for the process.
The working instructions are the easy guide for the operator to confirm each step in executing a task.
The working instructions are needed to guide the staff in performing a specific function or task.
PREMISES
Specify the requirements of location, design, constructions and maintenance of manufacturing premises with respect to the following:
prevention of contamination from surrounding environment and pests
prevention of mix-up of materials and products
facilities such as toilet, changing rooms, sampling areas and QC lab
defined areas for certain activities
wall, ceiling, drains , air intake and exhaust, lighting & ventilation, pipe work & light fitting
storage areas
EQUIPMENT
Describe the requirements of the design, installation and maintenance of the equipment and its support system such as ventilation system.
SANITATION & HYGIENE
Describe the sanitation and hygiene practices to avoid contamination of the manufacturing of products with respect to:
health condition of the staff;
good personal hygiene;
avoid direct physical contact with product;
restricted activities within controlled areas;
measures to prevent contamination by staff
PRODUCTION
Describe the control of manufacturing process with respect to the following:
Checking and Verification of Starting Materials
Traceability of starting materials to the product
Handling of Rejected Materials
Batch Numbering System
Weighing and Measurement
Production process of dry and wet products
Labelling and Packaging
Finished Product: Quarantine and Delivery
Module 2: Personnel
The greatest resource that a pharmaceutical company has is its personnel.
Pharmaceutical Company should ensure that there are sufficient qualified key personnel and staffs
who are adequately trained in the principles and application of GMP to ensure:
protection of the health of all personnel;
protection of the product from contamination; and
protection of product quality
The module will apply to all personnel in the pharmaceutical manufacturing facilities, such as:
Manufacturing
Quality Control
Warehouse, etc.
NUMBER OF PERSONNEL
Adequate number of qualified people with practical experience versus procedures,
processes, equipments
An individual’s responsibilities should not be so extensive as to present a risk to quality
There should be sufficient qualified personnel to carry out the task
KEY PERSONNEL
With Practical Experience
under professional guidance
able to take difficult decisions in a professional and scientific way,
resolve the problems encountered in manufacturing and QC
RESPONSIBILITIES
HEAD OF PRODUCTION
He/she should have authority & responsibility to manage production of drug preparations, w/c cover:
Production and storage according to appropriate documentation
Approval and implementation of production instructions, in-process QC
Evaluate production records; signed by designated person before passing to QC
Maintenance of production department, premises and equipment
Calibrations performed which are recorded and reports made available
Initial and continuous training of production personnel
GENERAL REQUIREMENT: TRAINING
There should be a written training programme, which has been approved by either Production or QA Head for:
all personnel whose duties take them into production; or
into control laboratories;
for others whose activities could affect the quality of the product; and
for staff in special areas
o e.g. working with hazardous materials
Training should be done before undertaking a new task.
The concept of QA must be understood and implementation should be fully discussed during training especially on the theory and practice of GMP.
Practical effectiveness should be periodically evaluated
e.g. form of quiz/tests, observation of work, or other ways of evaluating understanding)
Training records should be kept
Module 3: Premises
The location, layout and design of buildings should be suitable for the intended operations and should minimize the risk of cross contamination and errors during all aspects of manufacture, filling and packaging.
They should allow effective cleaning and maintenance in order to avoid build up of dust or dirt, and in general, any adverse effect on the product or the surrounding environment.
OBJECTIVES
To define that the area used for manufacturing should be suitably located, designed, constructed and maintained in such a way that processing, personnel and material flow are at minimal risk of contamination.
To identify the materials used for construction to permit effective cleaning and avoid build up of dirt or other conditions that may directly or indirectly affect the quality of products during their manufacture or storage.
PRINCIPLE
Facilities should be designed for:
logical flow of materials and people
adequacy of working space and orderly and logical positioning of equipment
smooth/crack-free/easy to clean interior surfaces
Production of cosmetics must be separated from the production of other products (e. g. drugs, devices)
Non-hazardous household products can share premises provided that care be applied to prevent cross contamination and risk of mix-up.
Painted line, plastic curtain and flexible barrier may be used to segregate.
DEFINED AREAS
There should be specific areas for:
Receiving of Starting & Packaging Materials
Sampling
Weighing/Dispensing
Gowning/ Change Room
Storage areas for approved raw material, packaging materials, and finished goods
Quarantine & Reject Areas
Processing
FLOORS
Solid concrete for warehouse
Solid concrete with epoxy or polyurethane resin finish is suitable for processing areas as it has a non-porous topping with non skid surface and retards bacterial growth.
Equivalent materials can be floor tiles with proper cleaning and sanitizing procedure
WALLS & CEILINGS
Block structural wall of high density, smoothly plastered, waterproofed by painting with acrylic or high polymer enamel
Cement boards:
Weather resistant
Termite & vermin resistant
No formaldehyde content
No asbestos content
JOINTS & FRAMES
The design of joints and frames should be such that cleaning and sanitation can be done easier
VENTILATION
Air should be appropriately filtered specifically in the processing and filling areas.
One pass filtration air or circulation for wet, non-powdered and dry preparations.
Dry or powdered product should have a dust collection system installed.
For the rest of the areas where there is product exposure, suitable ventilation is required.
LOADING & UNLOADING
Goods received and dispatched at the docks, bays, platforms or areas should be protected from dust, dirt and rain.
STORAGE AREA
Storage areas should be of sufficient capacity to allow orderly storage of various categories of materials and products with proper segregation. Status labeling of materials should be observed.
Storage areas should be of sufficient capacity to allow orderly storage of various categories of materials and products with proper segregation. Status labeling of materials should be observed.
QUARANTINE & REJECTED AREAS
Any system replacing physical quarantine should be given an equivalent security.
Reject area should be kept under lock and key.
WEIGHING & DISPENSING
The weighing of starting materials should be carried out in a separate weighing area designed for that use, complete with provisions for dust control.
CHANGE ROOM
Store working shoes separately.
Keep gowns in cabinet to avoid dirt and dust.
Soap for hand cleaning must be installed near the sink. Paper towels or hand drier should be provided whichever is suitable.
PROCESSING AREA
Adequate working space should:
permit the orderly & logical positioning of equipment and materials to minimize the risk of confusion,
avoid cross contamination and reduce the risk of omission or wrong application of any of the manufacturing or control steps.
INTERIOR OF PROCESSING AREA
Smooth, cleanable, easy to maintain and impervious to chemicals or cleaning materials.
Covings where floor meets walls may be observed.
Recessed light fittings where appropriate.
INTERIOR OF PROCESSING AREA
What should be avoided:
o Windows opening to the outside
o Ledges and recesses
Sliding doors must have proper cleaning procedure
PACKAGING AREA
Premises for filling/ packaging should be designed and laid out to avoid mix-ups or
cross contamination.
UTILITY STORAGE
A storage area for clean equipment used for production should be provided.
STORAGE OF CLEAN & IDLE EQUIPMENT
A separate room may be needed for storing clean, idle equipment which should be kept dry at all times.
Proper storing of hoses allowing them to dry should also be observed to prevent
retention of liquid.
Cabinet for clean equipments
Module 4: Equipments
Each manufacturer should assure that all production equipment and quality control
measurement equipment are:
suitable for the intended use in the design, manufacture, and testing
capable of producing valid results;
operated by trained employees; and
properly calibrated versus a suitable standard.
OBJECTIVE
To ensure the equipment and apparatus used for manufacturing process that must be made with stable and proper material, correct design, safe and easy to operate.
SCOPE
This module addresses the steps necessary to ensure that manufacturing equipment and laboratory apparatus continuously operates within the parameters necessary to produce a product that meets specifications.
BASIC PRINCIPLES
Equipment should be appropriate for its intended purpose and be appropriately designed, located, cleaned, maintained and correctly installed, to:
prevent contamination of subsequent batches of product using the same area or equipment.
prevent contamination of personnel or the environment;
prevent contamination of product by personnel or the equipment.
BASIC REQUIREMENTS
All equipment used to manufacture a product shall be appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use.
The degree of maintenance on equipment and the frequency of calibration of measuring equipment will depend upon the type of equipment, frequency of use, and importance in the manufacturing process.
DESIGN & CONSTRUCTION
Surfaces must not be:
o Reactive
o Additive
o Adsorptive
PIPES & PIPELINES
Fixed pipelines for the transfer of products and materials should :
o be clearly labeled
o indicate contents
o show direction of flow
Water, steam, pressure and vacuum lines where applicable should be installed:
o easily accessible
o clearly identified
o instrument monitoring control
The material quality and quantity that uses piping system should be monitored and checked periodically.
Pipelines for hazardous gas and liquid installation…
o should be clearly labeled
o and pipe connections should use the right materials
SAFETY DEVICES
All safety and regulator devices should be checked and calibrated regularly
LOCATION & INSTALLATION
Avoid congestion.
Properly identified.
Easily accessible during all phases of operation.
Equipment layout and design must aim:
- to minimize risks of error
- to permit effective cleaning
- to permit effective maintenance
And to avoid:
- cross-contamination
- dust and dirt build-up
- any adverse effect on the quality of products
Equipment must be installed to:
- minimize risks of error
- minimize risks of contamination
TYPE OF MATERIALS USED
Most of the pipelines should be used with Stainless Steel 316L as it is stable when in contact with the materials, during hot sanitation & disinfection.
Plastic pipelines may be cheaper in cost than stainless steel but the disadvantage of it is being unstable with hot sanitation and surface may not be perfectly smooth which poses a risk for germ contamination.
CLEANING EQUIPMENT
Cleaning protocol for trace back record
Cleaning status of the equipment should be indicated on the label
MAINTENANCE SCHEDULE
There should be established schedules to maintain, clean, and adjust equipment used in the manufacture:
have a written schedule;
where adjustment is necessary to maintain proper operation, have special instruction;
document the maintenance activities;
check periodically;
audit the activities and document the inspection.
CALIBRATION
The intent of the GMP Calibration requirements is to assure adequate and continuous performance of measurement equipment with respect to accuracy and precision
The equipment should be calibrated according to written procedures that include specific directions and limits for accuracy and precision. All results should be documented.
TRAINING PROGRAM
The training program should be established to assure that the personnel involved in execution, operation, calibration and preventive maintenance will understand and follow up all written Standard Operating Procedures and Equipment Work Instruction.
Training must be provided upon approval of each SOP or WI for the personnel that will be execute this particular procedure.
Module 5: Sanitation and Hygiene
High level of hygiene and sanitation shall be practiced in every aspect of manufacturing cosmetic products.
The scope of hygiene and sanitation covers personnel, premises, equipment, apparatus, production materials and containers, and environment.
Any source of contamination shall be eliminated through an integrated comprehensive program of sanitation and hygiene.
In all instances, the hygiene and sanitation procedures shall be periodically assessed to ensure that the effectiveness of the operation meets the requirements.
OBJECTIVES
The aim of sanitation and hygiene measures is to eliminate all potential sources of contamination and cross-contamination from all areas where the product quality is at risk.
CLEANING PRINCIPLES
Cleaning operations shall be performed in a manner to prevent contamination of materials & products.
Cleaning practices can be divided by:
“deep cleaning”,
“housekeeping cleaning”, and
“maintenance cleaning”.
All cleaning compounds and sanitizers shall be properly labeled and stored in a locked
compartment, away from production and storage areas.
Cleaning equipment and tools shall be supplied and be readily available for use. All cleaning
equipments shall be maintained and stored in such a way as not to contaminate product or
equipment.
BASIC HYGIENE
o Basic in any operation is personal hygiene.
o Bacteria causing diseases may be carried and transmitted to the manufacturing area and product by workers handling the cosmetic products.
GOOD PERSONNEL HYGIENE
Personnel must practice good personal hygiene.
regular bathing every day
brushing of teeth
washing hands before entering the production area
after visiting the toilet
after eating
after smoking
NO EATING, DRINKING & SMOKING
“No Eating”, “No Drinking”, “No Smoking”, and “No Chewing Gum” policy shall be strictly implemented as well as no spitting on the floor.
Food shall not be kept in production, warehouse or laboratory area.
PREMISES DESIGN for Sanitation
The design of the premises depends on the manufacturing activities. All areas should be designed in such a way that prevents the build-up of dirt and dust.
The plant facilities shall:
• provide sufficient space for equipment and storage of materials for the maintenance of sanitary operations and safe production.
• provide adequate lighting, ventilation or control equipment to minimize contamination
have an effective pest control program.
• Provide adequate screening or other protection against insects & pests.
Buildings / facilities should be so constructed that:
• floors, walls, and ceilings may be adequately cleaned and kept clean, and kept in good repair;
• floor must be hard, smooth and impervious, sloping sufficiently towards a drain thus allowing cleaning with water;
• grounds shall be kept clean that will protect the product against contamination, and to include proper storage of equipment, removing litter and waste;
• drains are kept to a minimum number. Their design must prevent the possibility of back-flow. Open channels should be easy to clean and sanitize.
SANITATION FACILITIES
Each plant shall be equipped with adequate sanitary facilities including, but not limited to:
• Water Supply
• Plumbing
• Toilet Facilities
• Hand Washing Facilities
• Rubbish Disposal
• Changing Facility or Locker
This should be sufficient, adequate in size and design, and properly installed for easy cleaning and sanitation processes.
Sanitation Facilities
RUBBISH DISPOSAL
Waste material should be placed in suitable container and regularly collected for disposal outside the production areas.
• Regular & timely collection of garbage
• Garbage bins must be properly covered at all times
• No food wrapper to be thrown in garbage cans inside the production area
• Do not use product shipping cases as garbage bins
Sanitation Facilities
CHANGING ROOM(S)
• Suitable changing facilities or locker should be provided at appropriate location for the storage of employees’ clothing and personal belongings
• Personal belonging shall be kept in lockers or drawers.
GOOD HOUSEKEEPING ADVANTAGES
• A Clean Workplace is High in QUALITY;
• A Clean Workplace is High in PRODUCTIVITY;
• A Clean Workplace Keeps COSTS Down;
• A Clean Workplace Saves TIME;
• A Clean Workplace Ensures EFFICIENT Delivery;
• A Clean Workplace Provides HEALTHY environment;
• A Clean Workplace is SAFE for people to work in;
• A Clean Workplace is High in MORALE.
EQUIPMENT SANITATION
SANITATION PRINCIPLES
Equipment should be easy to dismantle or remove to facilitate cleaning by non-corrosive materials.
Design, type, size and installation of equipment shall be in such a way as to avoid and prevent any contamination during use.
When choosing and buying machines, hygienic production and possibilities for cleaning and disinfection must be considered.
CLEANING PRACTICES
Cleaning operations shall be performed in a manner to prevent contamination of materials and products.
Only cleaning compounds and sanitizers authorized shall be used for cleaning.
All cleaning compounds and sanitizers shall be properly labeled and stored in a locked compartment, away from production and food storage areas.
Cleaning equipment and tools shall be supplied and be readily available for use.
Equipment and utensils should be kept clean.
CLEANING PROCEDURE
Written SOP’s shall be established specifying:
• areas, equipment to be cleaned
• cleaning and sanitization procedure for each area, equipment
• cleaning and sanitization frequency such as between individual batches, change over from one product to another, plant shutdown or new equipment
• precautions to minimize contamination and spread of microorganisms
• personnel assigned to do the cleaning
CLEANING METHOD
1. Foam: Foam is produced through the introduction of air into a detergent solution as it is sprayed onto the surface to be cleaned. Foam cleaning will increase the contact time of the chemical solutions, allowing for improved cleaning with less mechanical force and temperature.
2. High Pressure: High pressure cleaning is used to increase the mechanical force, aiding in soil removal. In high pressure cleaning chemical detergents are often used along with increased temperature to make soil removal more effective.
3. Clean in Place (CIP): CIP cleaning is utilized to clean interior surfaces of tanks and pipelines of liquid process equipment. A chemical solution is circulated through a circuit of tanks and or lines then returned to a central reservoir allowing for reuse of the chemical solution. Time, temperature, and mechanical force are manipulated to achieve maximum cleaning.
4. Clean Out Of Place (COP): COP cleaning is utilized to clean tear down parts of fillers and parts of other equipment which require disassembly for proper cleaning. Parts removed for cleaning are placed in a circulation tank and cleaned using a heated chemical solution and agitation.
5. Mechanical: Mechanical cleaning normally involves the use of a brush either by hand or a machine such as a floor scrubber. Mechanical cleaning uses friction for food soil removal.
FACTOR THAT INFLUENCE CLEANING
• There are 4 interrelated factors which affect the overall cleaning process.
• When designing cleaning procedures these factors need to be carefully considered:
o Cleaning Time
o Temperature
o Chemical being used
o Mechanical Forces
FUNDAMENTAL OF CLEANING
The following are the typical considerations when designing a cleaning and sanitization procedure:
- factors that influence cleaning (time, temperature, chemical concentration, and mechanical force),
- method of cleaning,
- type of dirt to be removed
CLEANING RECORD
• Cleaning and sanitization records/log books must be kept
• Operator shall record the area and equipment cleaned and sanitized
• Record signed and countersigned by another individual who checks the
cleanliness of the equipment/area.
SANITATION PRINCIPLES
The main objective of a cleaning program is to control microbial activity. Although an adequate cleaning program will eliminate nearly all the soil present, however, it will not destroy or remove all the micro-organisms.
And this requires a second step “sanitation”
Sanitation methods can be divided into two groups:
1. Non-chemical disinfection methods
2. Chemical disinfection methods
A well-planned, well-executed and controlled cleaning and sanitation program for rooms, machines, equipment and working area is very important to achieve a hygienic standard.
Cleaning and sanitation alone will not assure a hygienic standard, process and personal hygiene are equally important factors.
Module 6: Production
OBJECTIVES
To manufacture good & safe products and to deliver products with good efficacies
To standardize all actions related to production activities.
To ensure the consistency of product quality by using only approved starting materials
To identify production activities, enable follow up and traceability
To avoid cross-contamination and microbial contamination in production
To avoid any error in production
Production activities consist of the following:
receiving & recording of starting materials
sampling of starting materials
preparation of production documents, including master formula
weighing activities
cleaning & sanitization of equipment
preparation of bulk
filling & packing activities
reconciliation of production output
proper recording of each activities to ensure traceability of finished products
quarantine and delivery to warehouse
reprocessing, if necessary
PRODUCTION is defined as all activities starting from processing to packaging to obtain
finished products
PROCESSING is part of production cycle starting from weighing of raw materials to obtain a
bulk product
PACKAGING is part of production cycle starting from bulk product to obtain the finished
Product
STARTING MATERIALS consist of raw materials and packaging materials used in the
production of pharmaceutical products
MAIN GOALS
The main objectives of a pharmaceutical manufacturer are:
- to produce finished products from a combination of starting materials
- to look after all the materials which will influence the quality of finished product
compliance with GMP guidelines to avoid product being rejected or recalled
from the market.
MATERIAL REQUIREMENTS
All incoming materials should be quarantined immediately after receipt until they are
released for use in production
Raw materials should be stored under appropriate condition.
Storage condition should be controlled, monitored and recorded
Storage of materials should be orderly to avoid mix up and cross contamination
Ensure that there is an effective system in controlling stocks
Ensure that consumption of starting materials follows:
FIFO ~ First-In-First-Out, or
EEFO ~ Earliest Expiry, First Out.
Personnel in charge of raw material purchase should have sufficient knowledge of the
materials, products and suppliers of the materials
Raw materials should be purchased from qualified suppliers. Raw materials should have
approved specification and deliveries are accompanied with a certificate of analysis.
It is suggested to purchase raw materials directly from manufacturers or appointed distributors
Starting materials should be checked and verified for their conformity to specifications and be
traceable to the product.
Samples of raw materials should be physically checked for conformity to specifications prior to
release for use. Raw materials should be clearly labeled.
All materials received should be clean and checked for appropriate protective packing to
ensure no leakage, perforation or exposure to environment.
Deliveries of raw materials that do not comply with specification should be segregated and
disposed according to standard operating procedures
KEY CONSIDERATIONS
STARTING RAW MATERIALS
• Capability and Responsibility of Purchasing Personnel
• Supplier Credibility
• Checking of each consignment
• Clean and Properly labeled outer packing
• Any damage on the containers
• Different batches in one consignment
• Material Records and Proper Documentation
• Primary and printed materials control
• Handling of printed packaging materials
• Storage and transport to avoid mix-up
• Issued and returned packaging materials from production area
• Specific reference number for batch or consignment
• Checking and recording of packaging component
• Outdated or obsolete materials
QUALITY OF PACKAGING MATERIALS
The packaging of pharmaceutical products must provide protection:
• against all adverse external influences that can alter the properties of the product, e.g. moisture, light, oxygen and temperature variations;
• against microbial contamination and physical damage;
• against incorrect information and identification of the product.
The kind of packaging materials to be used must:
• not have any adverse effect on the product (e.g. through chemical reactions, leaching of packaging materials or absorption);
• be stable and product resistant (no change in properties, or affecting its protective function)
The final packaging material should be able to protect the product until its intended shelf-life.
REJECTED MATERIALS
Clearly Marked
Rejected materials should be clearly marked as such.
Stored separately in off-limits area
Access to the area should be controlled.
Actions:
rejected materials should be returned to the suppliers, destroyed or reprocessed;
the action should be described and defined in a procedure;
the action to be taken should be approved by authorized personnel;
the action and approval must be recorded.
WASTE MATERIALS HANDLING
• All waste materials should be properly handled
• Should be stored properly and in a safe place
• Toxic and flammable materials should be stored in a suitable designed, separated and enclosed area
• Should not be allowed to accumulate
VERIFICATION OF MATERIAL DELIVERY
• Starting materials should have been tested and passed requirements before these can be delivered to production:
- tested according to approved specification
• bear identification tag based on the status
• materials should be protected from leakage, contamination, and delivered in good condition
• containers should be cleaned prior to entry in the production area
• label should be placed on each weighed material
• quantity of weighed material is in accordance with the requirement in the written production documents
BASIC PRODUCTION PRINCIPLES
Starting materials should be tested and approved according its specification
Production equipment should be cleaned, safe, appropriate in size, and appropriate for product type to be manufactured
Operation on different products should not be carried out simultaneously in the same room, unless there is no potential risk of mix-up and contamination
All materials should bear clear labels and batch numbers
Limited access in production area, only authorized personnel
Handling of materials and products should be based on written instruction/procedure, and where necessary, recorded
All work instructions/procedures should be written and approved
Batch manufacturing records should be well recorded by qualified and responsible personnel.
PROCESSING GUIDANCE
There are several guidelines that should be followed prior, during and after each production activities. These are:
• Area clearance or lines clearance should be done, to avoid mix up of starting materials or finished products
• In-process and environmental controls should be carried out and recorded.
• Indication of failure of equipment or services should be monitored and only equipments in good condition should be available in the production area.
• Cleaning procedures should be written and approved
• Containers should be cleaned prior to use
Any deviation from requirements and expected result should be recorded and investigated prior to start of production and prior to release of the finished product
PROCESSING GUIDANCE
Any significant deviation from the expected yield should be recorded and investigated.
Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.
Pipes used for conveying distilled or deionized water should be sanitized according to written procedures
Measuring, weighing, recording, and control equipment should be serviced and calibrated at pre-specified intervals and records are maintained.
Repair and maintenance operations should not present any hazard to the quality of the products.
PACKAGING GUIDANCE
Minimize risk of cross-contamination and mix-ups
Different products should not be packaged in close proximity unless there is physical segregation.
Line clearance in packaging area should be done.
Packaging line should bear the product name and batch number being produced
An appropriate procedure should be developed if labeling is delayed to avoid any mix up or mis-labeling.
Verification of correct performance of printing done separately checked and recorded.
Special care should be taken when cut labels are used and when overprinting is carried out off-line, and in manual packaging operations.
Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.
On-line control of the product during packaging
Samples taken away from the packaging line once opened should not be returned.
Return of reworked finished products into the lot can only be done after special inspection, investigation, approval by authorized personnel.
Any unusual discrepancy during reconciliation should be investigated before product release
Any unused batch-coded materials should be destroyed and recorded.
Excess labels and packaging materials should be returned to store; properly tagged/labeled and recorded
WEIGHING & MEASUREMENT
Weighing should be carried out:
- in defined areas
- using calibrated equipment.
All weighing and measurement carried out should be:
- recorded
- counter checked
PREVENTION OF CONTAMINATION
Prevention of contamination should be done in every step of manufacturing processes
Type of contaminant can vary, starting from dust, gases, vapors, spray, residues from equipment, insect, microbes, or may come from operators clothing.
Area where some susceptible products are processed, such as product for babies or products applied around the eye area should be monitored periodically for its microbial content.
Cross-contamination should be avoided through proper application of preventive measures
Measures to prevent cross-contamination and their effectiveness should be checked periodically.
IN-PROCESS CONTROL
Done within the production area and by production people and/or Quality Control
Should be recorded and done as per approved/written SOP
Sampling done to verify:
• physical aspects (weight, volume, amount, etc.)
• text on labels
• other performance requirements
Sampling maybe conducted based on need:
• during processing activity
• during packaging (filling & packing) activities:
o random,
o sequential, or
o statistical
Samples taken away from the packaging line should not be returned if containers were opened
Record of in-process control should be part of the BMR.
LINE CLEARANCE
• line clearance should be done prior to processing and filling operations
• prepare a clearance check list for each operation
• material from previous batch should be removed from the line
• filling machine should be connected to the right outlet of the bulk storage tank
• number of personnel should be enough to operate the line
• each personnel has clear understanding of their roles and responsibilities in the processing or filling operation
• processing line should be clearly identified and labeled with the name of the product and batch number
• filling lines should be physically identified with the product name, size, batch no, and if needed the destination of products
RECONCILIATION
Any deviation from the procedures should be avoided as much as possible. If deviations occur, they should be approved in writing by a designated person, with the involvement of the quality control department.
Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.
These are some points to be considered in the reconciliation of the batch: quantity of starting materials, output of finished products, machine efficiency
All activities concerning reconciliation should be conducted based on written standard operating procedures.
BATCH NUMBERING SYSTEM
• A product identification number/batch number should be assigned to:
o every finished product
o every bulk and semi finished product
o which enables the history of the product to be traced.
• A batch numbering system should be unique
o specific for the product
o non repetitive for the same product
• Creation of batch number should be based on written guideline (SOP)
• Records of batch number should be kept and maintained
o for every finished product
o until at least 1 year after the expiry date
o for traceability factor
• A batch number may give information on :
o date and year of production
o country, manufacturer or subcontractor
o sequence of production
• The batch number should be printed on:
o primary packaging
o secondary packaging (as necessary)
HANDLING OF REJECTION OUTPUT
Rejected product should be properly labeled and physically separated
Investigation of the root cause of rejection should be done by production and assisted by quality control
SOP in handling rejected product should be established, written and approved
If rework can be done, written procedure should be prepared by production and approved by quality control
Stability of reworked products should be verified and if necessary additional testing should be performed
REPROCESSING
Reprocessing is a delicate/tedious activity for a rejected product.
There should be a written policy which clearly states that such action is allowed to be done.
Reprocessing of rejected product should only be done in exceptional cases.
It should only be allowed if the quality of the product is not negatively affected and the product quality still complies with the specifications.
It should consider additional testing of reprocessed product, e.g. stability testing of the batch.
Complete records should be maintained for reprocessed product
A reprocessed product should be given a new batch number.
FINISHED PRODUCT STATUS
All label concerning with the status of finished products should be shown clearly
Quarantine status can be in the form of:
o physical (rope, racks layers, pallet)
o computer system
Rejected products :
o identified and physically separated
o taken out from the stock
o further process (destruction, reworked, etc)
RETAINED SAMPLES
Sample retention program should be carried out for reference and retesting for stability
evaluation and in case of product complaint.
PRODUCTION DOCUMENTS
Production documents of each cosmetic product should consist of:
Master Formula
Batch Manufacturing Record (BMR)
Record of Quality Control
MASTER FORMULA
Master Formula is compilation of all information, related to all aspects involved in the production of a pharmaceutical products.
One Master Formula is applicable only for one type of product
Content of a Master Formula:
Master Formula number
Product name and product code/number.
Issue date & name of the originator
History of the Master Formula in case of revision
Formula composition, both for raw & packaging material (raw materials should be written by INCI name)
List of equipment used
Manufacturing procedure, including in-process control with their limit in processing and packaging, where applicable
Specification of starting materials, bulk, and finished products
Specification of intended packaging materials, and storage condition.
Components and assembly method of components in a finished product
BATCH MANUFACTURING RECORD
Batch Manufacturing Record should be prepared for each batch of product.
Each BMR should include the following:
Name of product
Batch formula
Brief manufacturing process
Batch or code number
Date of the start and finish of processing and packaging
Identity of individual major equipment and lines or location used
Records of cleaning and sanitation of equipment used for processing as appropriate
In-process control and laboratory results, such as pH and temperature test records
Packaging line clearance inspection records
Any sampling performed during various steps of processing
Any investigation of specific failure or discrepancies
Results of examinations on packed and labeled products
02-2010
PRODUCTION
(Section 6)
Introduction:
This module is to assist the manufacturer on the key concept of production.
Scope:
Basic requirements of production essential to product quality.
Objectives:
To understand basic requirements of production
To be able to disseminate the information on these requirements
To provide understanding on these requirements to production personnel and management
To provide standard operating procedures
Organizational Structure:
The organizational structure of the company shall be such that the production and the quality control manager are headed by different, neither of whom shall be responsible to the other.
Each shall be given full authority and facilities necessary to execute respective duties effectively.
Neither shall have any interests outside the manufacturer’s organization that prevent or restrict their dedication to the assigned responsibilities or which may be considered to entail a conflict of interest.
Key Personnel:
Key Personnel (full-time) positions include:
Head of Production
Head of Quality Control
(Heads of Production & Quality Control should be independent of each other)
Head of Quality Assurance
Note: Large Organization – may be necessary to delegate some of the functions;
however, the responsibility cannot be delegated.
Organizational Structure:
Basic Requirements:
Production shall follow defined procedures capable to provide assurance of consistently yielding drug products that conforms to their specifications.
6.1 Basic Manufacturing Requirements:
6.1.1 Equipment shall be:
- Technically Suitable,
- Well Sited (so as not to interfere with other operations),
- Easy to Clean and Maintain
The design sitting and operation of equipment shall ensure that no contamination from foreign materials such as rust, lubricants, abraded particles or foreign ingredients should occur.
There shall be an adequate number of personnel at all levels having knowledge, skills, and capabilities relevant to their assigned functions, in good mental and physical health to be able to execute their duties.
Basic Requirements:
6.1.2 A high standard of factory sanitation and personal hygiene is necessary to
achieve the objectives of protecting:
- each product from contamination by the environments or by the operations, and
- protecting products from cross contamination with other products
Emphasis in this important area shall be placed on written programs to ensure that the
steps have been logically thought out and validated.
6.1.3 The manufacturer shall clearly define its system of information and control.
The documentation system shall:
provide unambiguous sections to be followed,
provide confirmation of performance,
allow calculation to be checked, and
to allow the accountability, and
traceability of operators, materials and batch disposition.
6.1.4 Manufacturing facilities and methods shall be designed to prevent
cross-contamination.
6.1.5 There shall be:
sufficient space provided to minimize clutter, and
untidy work practices to assure orderly materials receivals, warehousing and processing activities.
The layout of rooms, corridors and areas, shall provide for logical movement of
materials & personnel w/ minimal traffic & for operations to be carried out in defined areas.
Generally:
1. Production should be performed and supervised by competent people.
2. All handling of materials and products, such as:
- receipt and quarantine - sampling
- storage - labelling
- dispensing - processing
- packaging - distribution
should be done in accordance with written procedures or instructions and, where necessary, recorded.
3. All incoming materials should be checked to ensure that the consignment corresponds to the
order. Containers should be cleaned where necessary & labeled with the prescribed data.
4. Damage to containers and any other problem which might adversely affect the quality of a
material should be investigated, recorded and reported to the Quality Control Department.
5. Incoming materials and finished products should be physically or administratively quarantined
immediately after receipt or processing, until they have been released for use or distribution.
6. Intermediate and bulk products purchased as such should be handled on receipt as though they
were starting materials
7. All materials and products should be stored under the appropriate conditions established by the
manufacturer and in an orderly fashion to permit batch segregation and stock rotation.
8. Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure hat
there are no discrepancies outside acceptable limits.
9. Operations on different products should not be carried out simultaneously or consecutively in the
same room unless there is no risk of mix-up or cross-contamination.
10. At every stage of processing, products and materials should be protected from microbial and
other contamination.
11. When working with dry materials and products, special precautions should be taken to prevent
the generation and dissemination of dust. This applies particularly to the handling of
highly active or sensitizing materials.
12. At all times during processing, all materials, bulk containers, major items of equipments and
where appropriate room used should be labeled or otherwise identified with an indication of
the product or material being processed, its strength (where applicable) and batch number.
Where applicable, this indication should also mention the stage of production.
13. Labels applied to containers, equipment or premises should be clear, unambiguous and in
the company’s agreed format.
It is often helpful in addition to the wording on the labels to use colors to indicate status
(for example, quarantined, accepted, rejected, clean, …)
14. Checks should be carried out to ensure that pipelines and other pieces of equipment used for the
transportation of products from one area to another are connected in a correct manner.
15. Any deviation from instructions or procedures should be avoided as far as possible.
If a deviation occur, it should be approved in writing by a competent person, with the
involvement of the Quality Control Department when appropriate.
16. Access to production premises should be restricted to authorized personnel.
17. Normally, the production of non-medicinal products should be avoided in areas and with the
equipment destined for the production of medicinal products.
Process Validation
A means of ensuring and providing documented evidence that processes are capable of consistently producing a finished product of the required quality.
Objectives:
To understand the Basic Principles of Process Validation
To understand the ASEAN guidelines on Process Validation
Know the Data Submission Requirements of Manufacturing Process Validation
Validation:
The documented act of demonstrating that any procedure, process, and activity will consistently lead to expected results. It includes qualification of systems and equipments.
Phases of Validation:
Phase 1: Pre-validation Phase or Qualification Phase
- Covers all activities relating to product research and development,
formulation, pilot batch studies, scale-up studies, establishing stability
conditions, storage and handling of finished dosage forms, equipments
qualification and documentation.
Phase 2: Process Validation Phase
- Designed to verify that all established limits of the Critical Process Parameters
are valid and that satisfactory products can be produced even under the
“worst case” conditions.
Phase 3: Validation Maintenance Phase
- Review of all process related documents to assure that there have been no
changes, deviations, failures, modifications to the production processes, and
that all SOP’s have been followed including change control procedures.
Why Process Validate?
Quality, safety and efficacy must be designed and built into the product.
Each step of manufacturing process must be controlled to maximize probability that finished product meets all quality and design specifications.
Quality cannot be inspected or tested into finished product.
Key element in assuring that quality assurance goal’s are met.
May reduce the dependence upon intensive in-process and finished product testing.
Elements of Process Validation:
Prospective Validation – A validation conducted prior to the distribution of either new
product or product made under a revised manufacturing process where revisions may affect the product’s characteristics.
Regulatory Requirements:
1. Three (3) consecutive full production batches which are successfully validated.
2. Batch size is minimum 100,000 unless justified.
Concurrent Validation – A validation carried out during routine production of products
intended for sale.
Regulatory Requirements:
1. Applicable to orphan drugs.
2. Prior consent from DRA before submitting the application for product registration.
Retrospective Validation – Validation of a process for product that has been marketed
based upon accumulated manufacturing, testing and control data.
Regulatory Requirements:
1. 10-20 batches should be studied.
2. Must be of the same manufacturing process used.
3. Demonstrate that the manufacturing process is under control.
Source of Data:
- Trend Analysis - Batch Documents
- Process Control Charts - Maintenance Log Books
- Finished Product Test Results - Stability Test Results
Re-Validation
• Provides the evidence that changes in a process and/ or the process environment that are introduced do not adversely affect process characteristic and product quality.
• Changes that may require re-validation.
o Changes in raw materials physical properties that may affect the process or product.
o Changes in the source of active raw material.
o Changes in packaging material (primary container/ closure system).
o Changes in the process.
o Changes in the equipment. Changes of equipment which involved the replacement of equipment on a “like for like” basis would not normally require a revalidation except that this new equipment must be qualified.
o Changes in the plant/ facility.
o Variations revealed by trend analysis.
Change Control
= A written procedure that describes the action to be taken if a change is proposed to facilities,
materials, equipment, and/or processes used in the manufacturing, packaging, and testing of
drugs, that may affect the quality or support system.
Changes in Validated Process
• Minor Change – changes that do not affect the quality of the finished product. These
changes do not require regulatory approval.
• Major Change – changes that would have signified impact on the quality of the finished
product. These changes require regulatory approval.
Guideline on Submission of Manufacturing Process Validation:
• Data Submission Requirements
• Option 1: When process validation is completed.
- Validation report on three (3) consecutive successfully validated production batches.
• Option 2: When submission of process validation data is not at the time of application.
- Development of pharmaceutics report;
- Validation report on 1 pilot batch or Validation Scheme.
- Undertaking that 3 consecutive full production batches are successfully validated before the product is marketed.
- To submit the report to Drug regulatory Authority within a specified time; or make information from these studies available for verification post authorization by DRA according to national procedure.
• Option 3: Product that have been approved by reference agencies.
- Validation report on 3 consecutive successfully validated production batches.
- Declaration statement that the same pre-approval dossiers pertaining to process validation that have been submitted to reference regulatory agency are submitted to DRA for evaluation.
Contents of Validation Protocol
• Description of the Process
• Description of the Experiment
• Details of the equipment/facilities to be used
• Variables to be monitored
• Samples to be taken – where, when, how and how many
• Product performance characteristics/ attributes to be monitored
• Test methods
• Acceptable limits
• Time schedules
• Personnel responsibilities
• Details of methods for recording and evaluating results including statistical analysis
Production
- Contamination -
Objective:
To help the production personnel to conform with the requirements needed to be GMP complaint – in the aspect of Contamination in Production.
Contamination – The presence in a drug product of any contaminant. The undesired
introduction of impurities of a chemical or microbiological nature, or of foreign matter; into or onto a raw materials, intermediate, or API during production, sampling, packaging or repackaging, storage or transport. Personnel/ People is the main source of contamination.
Types of Contamination:
1. Particulate Contamination – presence of particles that does not belong to the product.
Samples of Particulate: Hair, Lint, Fibers etc…
Dirt & Dust left on equipment that has been improperly cleaned
Size of particulates that are visible to the eyes: Hair (diameter) = 100-500 micron
Ordinary Dust = 100 micron
Metallurgical Dust = 100 micron
2. Due to Microbial Contamination – contamination that can’t be seen thru the naked eye.
3. Cross-Contamination – mixing anything that’s not called for in the batch record that will
contaminate the components… the batch… and ultimately the product itself.
Contamination of a starting material or of a product with another material or product.
GMP Regulations on Contamination
Since the air, water, personnel and all surfaces that come in contact with product during the manufacturing process are all potential sources of contamination, regular monitoring of the manufacturing environment shall be instituted to assure that the risk of contamination is detected early and corrective actions are undertaken.
• Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, product, product residues or documents not required for the current operations.
• Intermediate or bulk products should be kept under appropriate conditions.
• Any necessary in – process control & environmental control should be carried out & recorded.
• Intermediate or bulk products should be kept under appropriate condition.
Cross-contamination should be avoided by appropriate technical or organizational measures like the following:
a. production in segregated areas (required for products such as penicillins, live vaccines
live bacterial preparations and some other biological), or by campaign (separation in time) followed by appropriate cleaning;
b. minimizing the risk of contamination caused by recirculation or re-entry of untreated
or insufficiently treated air;
c. keeping protective clothing inside areas where products with special risk of cross-
contamination are processed;
d. using cleaning and decontamination procedures of known effectiveness, as ineffective
cleaning of equipment is a common source of cross-contamination;
e. providing appropriate air-locks and air extraction.
Contamination may include not only carry over from a previous product or residual cleaning solvents, but also detergents and surfactants. Firms need to establish limits that reflect the practical capability of their cleaning processes, as well as the specificity of the analytical test method.
When determining the acceptance limit in cleaning process, relevant factors generally include the following:
1. Evaluation of the therapeutic dose carryover;
2. Toxicity of the potential contamination;
3. Concentration of the contaminant in rinse and swab samples;
4. Limit of detection of the analytic test method; and
5. Visual examination
Weighing/ Dispensing
Objective:
To help the Production personnel to conform with the requirements needed to be GMP complaint – in the aspect of Weighing/ Dispensing in Production.
Dispensing:
The activity of weighing, counting or measuring and checking of starting materials and issuing these to the appropriate production personnel; details of the activity being duly and properly documented.
Every pharmaceutical manufacturing plant features an area in which raw materials are weighed and transferred to clean containers. This area goes by various names, including Weighing, Weigh Room, Central Weigh, Pharmacy, Dispensary, Dispensing, Fractionation and Subdivision. No matter what it’s called, its design is essential.
Three basic principles that should be considered in the design of any pharmaceutical weigh room:
1. Unidirectional flow of materials and personnel.
2. Segregation between hazardous and non-hazardous materials.
3. Separation of storage and manufacturing items and spaces.
In the past, convenience dictated the placement of weigh rooms, traditionally located right near warehouses where materials were stored. Today, the weigh room is viewed as the entry point to manufacturing and the transition point for materials coming from the warehouse and entering process areas, so specific criteria will determine the best location.
Therefore careful attention to design, layout and operation are essential.
The typical weigh room is made up of three sections:
1. raw material staging,
2. weighing and
3. work-in-process staging
GMP Regulations on Weighing and Dispensing
The methods for handling, weighing, counting and dispensing materials shall be included in written procedures.
All issuances including those for additional materials for production orders already dispensed shall be properly documented.
Only materials which are approved by quality control can be dispensed.
To avoid mix-up, cross-contamination, loss of identity and confusion, only the relevant materials shall be within the dispensing areas one at a time.
After weighing, dispensing and labeling, the materials shall be transported and stored in a manner that will preserve its integrity until further processing.
Each container must be cleaned prior to entry into the dispensing area.
Prior to weighing and dispensing, each container of raw materials shall be checked for proper labeling, including the approval from quality control.
Capacity of weighing and measuring equipment used shall be appropriate to the amount of materials to be weighed or measured.
For any weighing or measuring operation, two persons shall independently verify the correctness of the identity and amount of weighed or measured materials.
Weighing and dispensing areas shall be maintained in a clean condition.
Weighing and dispensing operations shall be carried out with clean equipment.
Dispensed materials shall be rechecked for identity and accuracy and signed by the production supervisor or equivalent prior to delivery to the production area.
If there is a balance of the material dispensed it must be brought back to its original storage area with label, properly sealed and with the QC approved sticker.
The weight or measure is correct as stated in the batch production records.
Dispensed materials must be labeled indicating:
1. Material name with its batch/ lot number.
2. Batch/ Lot number of the product to be processed.
3. Quantity weighed.
4. Signature of the weigher and the checker.
5. Date when the materials are weighed.
Another control that is used by some firms includes:
- Assurance that a dispensed raw material does not end up in the wrong batch; locked portable cages are being used and only pertinent cages are permitted in the room at the same time. Others used “kits” or “wrapped” materials per batch of dispensed materials.
- For an automated system that do not include checks on component quality control release status and proper identification of containers it is not permissible to omit second person component weight check of scales are connected to a computer but for a validated automated system with barcode reader that registers the raw materials identification, lot number and expiry date and that is integrated with the recorded accurate weight data, it is permissible omit second person component weight check.
How long in advance can the raw materials be weighed?
It is acceptable to weigh the raw material (RM) a few days prior to the scheduled date of production. However, the firm should be able to demonstrate that the materials and design of the containers in which the RM are weighed and kept will not alter their quality; the characteristics of the RM must also be taken into consideration.
“GMP in the Production of Liquid Products”
Basic GMP Principles for dry products apply as well to the GMP for liquid products’ manufacture, except for one or more aspects:
Equipment:
Equipments should be suitable, easy to clean and constructed of materials which will not become additive or reactive with the product materials.
• Tanks should be constructed of 304 or equivalent stainless steel.
o Polished Inside/Out
o Equipment with flush valve and capable of complete drainage
o Shall have filtered automatic vents
• Pumps and filters shall be of sanitary construction.
o Easy to disassemble and clean
• Sufficient racks for sanitary storage of utensils, dipsticks, sanitary pipings and flexible hose shall be provided (no wooden or wooden handled utensils are permitted).
• Quick coupling, sanitary fittings shall be used throughout the area.
• Insect-o-cutors or approved equivalents shall be provided.
• Equipment shall have appropriate facility for identification and be numbered so as to enable the keeping of equipment log.
• Tanks fitted with outside sight glasses are not permitted.
• Adequate number of identified sanitary trash containers shall be supplied.
Premises/ Environment
• Walls must insulate the area in which liquids are to be compounded, must be smooth, non-porous, non-dusting and free of peeling paint.
o Pipes and equipments should not be placed close to the walls so as to preclude proper clearing
• Windows
o No operable windows
o Windows on outside walls are permitted provided that they are without ledges which could produce a dust contamination hazard
Are smoothly grouted, screened
Room is maintained under positive pressure filled air supply
• Doors
o Shall be self-closing
o Shall be equipped with windows so as to eliminated hazards to personnel
• Ceilings should prevent contamination of the product by dust, foreign matter or condensate from overhead
o Overhead should not have open joints, exposed pipes or ledges of any kind unless special provisions are taken to preclude the possibility of contamination materials in process by dust failing from the ledges so formed
o Unsealed asbestos board, fiberglass panels and porous acoustics materials are not acceptable ceiling
• Floors
o Shall not constitute any hazard of attraction or cross contamination because they are cracked, porous or otherwise constructed or irregularly maintained so as to offer harborage for microorganism.
o Epoxy-sealed concrete, sealed hardened concrete are acceptable for floor
o Coving is to be used where walls join floors so as to eliminate cracks and right angels conducive to trapping foreign materials
o No pipes or equipment should be placed so close to the floor as to preclude proper cleaning
• Drain
o All floor drains should be trapped and vented so as to prevent back siphonage and/or passage of sewer into the operating area
• Space/ Storage Facilities for Equipment
o Shall be adequate so as to eliminate cross contamination or a product mix up
o Shall be adequate for storage facilities for utensils and unused equipment
• Air conditioning/air handling system
o Internal atmosphere shall be controlled
o Sufficient ventilation provided so as to prohibit build up of vapors and moisture which could be detrimental to the health/ safety of operators
o Air supplied to the area for ventilation must be filtered through a filter not greater than 10 microns and an efficiency of 80%
o Must be positive pressure in the area
• Was-up Area
o Shall be provided for washing equipment and utensils
o Shall be supplied with hot/ cold potable water, DI water of microbiological purity meeting the company standards
o Wash rack of sink, hoses, spray nozzles, detergent mixing vessels as appropriate for the need
o Adequate provisions for the orderly storage of hoses and utensils shall be supplied
o Non-potable water system shall not be permitted
o Bar soap is prohibited
o Steam at one atmosphere is desirable
• Lighting shall be adequate for good visibility – an intensity of 6 foot candles at work surfaces is recommended
o Pendant light fixtures shall be prohibited, except for explosion proof housing where required by local laws or mandated by product mix
o Incandescent bulbs and fluorescent tubes shall be mounted
Process
• Production of liquids shall be use closed system
• Mixing and filling processes shall be validated
• Chemical and microbiological quality of the water used shall be specified, monitored and documented
• Special care shall be taken at the beginning of a filling process, after stoppages and at the end of the process to ensure that homogeneity is maintained
• When the finished bulk is not immediately filled/ packaged, the maximum period of storage and the storage condition shall be specified and adhered to
• Prior to filling/ packaging of the bulk held in storage for a period that has exceeded the maximum period, a complete testing of the bulk shall be done to ensure that the product quality has not been affected
• Care shall be taken to maintain the homogeneity in the case of mixture, suspensions during filling and the dispersion characteristics
• The step by step procedures indicated critical in the production shall be documented as having been checked/ dated by the process operator
Quality Control
• Environmental Control – Prior to the Filling Process
o Environmental quality of the room shall have been determined and monitored (plate count)
o The room shall have been cleared for presence of any other drug product
o The cleanliness of the room is to be checked
• IPC of the bulk shall have been determined, such as:
o Physical appearance and other characteristics like color, odor/ taste
o Clarity at final filtration in the case of solutions
o Dispersion characteristics or suspendability characteristics in the case of suspensions
o pH
o Specific Gravity
o Assay of the active components
• During filling, a regular check of
o Volume of liquid filled
o Cap application/ retention torque
o Labeling
• Finished Product
o Complete testing of the product against product specifications
o Microbiological Test
• Process Water
Purified water USP is a basic starting material for all products but most notably in relatively big quantities for liquid products
o Process used to treat water to come up to USP standards can either be by
Steam Distillation
De-Ionization
Reverse Osmosis
o Process treatment of water has to be validated and process water quality to be controlled and monitored
“Sterile Production”
Environmental Controls:
A. Area Entry
B. Materials Movement and Storage
C. Air Quality
D. Gowning Practices
E. Sanitation and Hygiene
F. Behavior
G. Area Clearance between batches
H. Area Exit
Facility Design:
Design features for manufacture of sterile products
1. Ensure that the areas of sterile product contact components are to be prepared and which products are to be processed, filled and sealed should be segregated from other manufacturing areas and not used for any other procedures.
2. These areas should be designed, operated and managed as to minimized microbial and particulate contamination of products throughout processing.
3. The design of sterilizing facilities should preclude mix-up between untreated and treated (sterilized) materials.
* Precaution to minimize contamination should be taken during all processing stages, including
the stages before sterilization.
Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation.
• The flow of personnel, materials etc. should be optimized to prevent the potential contamination.
• The no. of personnel in an aseptic processing room should be minimized.
Products produced from Sterile Materials:
• Segregated areas are required for the following operations:
o depacking component from containers
o equipments and component washing
o processing
o filling and sealing of immediate containers
o airlock or other separated area, connecting gowning and filling room
o gowning room for changing into sterile working clothes prior to entering the sterile area
Clean Rooms:
• Should be provided with suitable anterooms or equivalent separation facilities through which staff or articles may enter or leave the area.
o Suitable changing areas should be
Arbitrarily divided into a “dirty section” (adjacent to the entry to the clean room) to assure proper gowning procedures.
A “step-over” bench should be made available to assist in change procedures and to provide the physical division between each end of the change area.
o Wash facilities should be provided in these anterooms.
• The design of the facility should assure that all areas supplied with HEPA filtered are positive air pressure differential to ambient air pressure and the sterile filing area is maintained at a positive pressure differential to immediately adjacent areas.
• There are specific air cleanliness requirements for different activities conducted in a clean room suite of rooms.
Classifications I: Terminally Sterilized Products
Product Type Preparation of Solution Filling of Solution
SVP and LVP 10,000 100/ 10,000
SVP and LVP 100,000 (Closed Container) 100/ 10,000
Other 10,000 10,000
Classifications II: Sterile Filtered Products
Product Type Preparation of Solution Filling of Solution
SVP/ LVP 10,000 100/ 100
SVP and LVP 10,000 100/ 10,000
SVP and LVP 100,000 (Closed Container) 100/ 10,000
Other 10,000 100/ 10,000
Products produced from Sterile Materials:
- Where a company is utilizing the one facility for both aseptic and terminally sterilized product then the company should operate to the higher standard of cleanliness at all times.
• There should be separate rooms with appropriate grade of clean filtered air for container and closure preparation and for batch compounding.
• There should be a “cascade” of air pressure values between the sterile manufacturing area and adjacent areas.
• Should be effectively flushed with air supplied under positive pressure and delivered through HEPA air filters located where the air enters the processing environment.
o Air inlets should be remote from the air outlets in order to achieve effective flushing of the room space to allow critical operations to be located in the least contaminated stream of air.
o Air outlets should be at low level.
• Should contain the minimum of “dead” space,
o Space not effectively flushed with clean air, the minimum of obstructions to flow of clean air, such as fittings, ledges and shelves and no extraneous equipment.
o The design materials and constructions should prevent access of which has not been filtered.
Continuous Monitoring Program:
Test Class Max. Time Interval
Particle Count A/ B/ ISO 5 6 months
C/ D/ > ISO 5 12 months
Air Pressure Difference All classes 12 months
Air Velocity All classes 12 months
Air Exchange All classes 12 months
Air Flow Pattern All classes 24 months
• Microbiological Monitoring
o Monitoring and Control Procedure should be available
Exposure of settle plates
Use of air sampling devices
Use of contact plates or swabs
“Production Premises”
1. Exposed Surfaces
- Smooth, impervious, unbroken to minimize shedding, accumulation of particles or organisms and to permit repeated application of cleaning agents and disinfectants.
- Recesses, edged, shelves, cupboards and equipment should be kept to a minimum to facilitate cleaning.
2. Doors
- No uncleanable recesses
- Sliding doors not acceptable
3. Ceilings
- sealed to prevent contamination from the space above them.
4. Sinks and Drains
- Not allowed in environment A and B
- Other environment, should be fitted with air breaks
- In lower grades should be fitted with traps or water to prevent back flow
5. Changing Rooms
- Should be designed as airlocks
- Should provide physical separation of the different stages of changing to minimize microbial and particulate contamination from protective clothing
- Separation changing rooms for entering and leaving clean areas
- Washing facilities provided only in the first stage of the changing rooms
- Flushed with filtered air to have a classification in the “at rest” state similar to the grade of the area into which it leads.
“Production Personnel”
1. Should be selected with great care and be effectively trained.
2. Should know the basic elements of microbiology & importance of personal hygiene & sanitation
3. Those with lesions on exposed body parts are not permitted to work in aseptic production.
4. Should not wear wrist watches, make-up and jewelry in clean areas.
5. Requires periodic health checks.
6. Number of staff therefore within the aseptic processing area should be kept to the minimum number required to efficiently carry out the designated tasks.
7. Reducing Contamination from Personnel.
- The most effective way of reducing contamination from personnel is to seal the contaminants within a “package”.
“Production of Semi-Solid Preparations”
Introduction:
Semi-solid constitutes a significant proportion of pharmaceutical dosage forms.
Definition: dermatologically products of semi-solid consistency which are applied to skin
for therapeutic protective action or cosmetic function.
They are intended for localized and systemic drug delivery and served as carriers for drugs that are topically delivered by way of the skin, cornea, rectal, tissue, nasal mucosa, vagina, buccal tissue, urethral membrane and ext. ear lining.
Types of Semi-Solid Dosage Forms:
a. Ointments e. Jellies
b. Creams f. Suppositories
c. Gels g. Foams
d. Pastes h. Poultries
“Ointments”
Definition: Ointments are semisolid preparations for external application to skin or mucous
membranes which softens but does not melt upon application to the skin.
Therapeutic Use: Skin protective and emollients
Primary Use: Vehicles for the topical application of drug substances.
Ointment as a Vehicle:
1. Emulsion Bases: or Hydrophilic or Water removable ointment bases.
2. Oleaginous Bases: includes the early ointments consisting almost entirely of
Vegetable (olive oil, cottonseed sesame, persic, etc.) and animal fats as well as those containing petrolatum hydrocarbons.
Since animal fats and vegetable oils are mixtures of glycerides, they undergo changes on exposure to light, air and elevated temperature causing decomposition with resulting undesirable rancid odor.
Antioxidants and other Preservatives are therefore indicated.
3. Hydrocarbon Bases: include ointments prepared from petrolatum or liquid
petrolatum wax or other stiffening agents e.g. White ointment USP. There is a
wide range in the melting point of petrolatum. It is generally preferably to obtain
a product which melts in the upper temperature limits. They do not become
rancid unlike the oleaginous bases.
4. Absorption Bases: denotes the water-absorbing properties (hydrophilic-anhydrous
bases which have the property of absorbing several times their weight of water
and still retains its ointment-like consistency forming emulsions) E.G. Anhydrous Lanolin USP (W/O Emulsion)
Pastes: Basically ointments into which a high % of insoluble solid has been added.
Paste makes particularly good protective barrier when placed on the skin
Forms an unbroken relatively water impermeable film
The solid they contain can absorb and thus neutralize certain noxious chemicals before they reach the skin.
Difference between Paste and Ointment:
o Less penetrating, less macerating and less heating than ointment
o With opaque film and therefore, an effective sun block
Pastes are less greasy because of the absorption of the fluid hydrocarbon fraction to the particulates. Pastes are usually prepared by incorporating solids directly into a congealed system by Levigation with a portion of the base to form a paste like mass. The remainder of the base is added with continued levigation until the solids are uniformly dispersed in the vehicle.
Creams: Viscous semi-solid emulsion system with opaque appearance as contrasted with
translucent ointments. Consistency and rheological character depends weather the cream is w/o or o/w.
Properly designed O/W creams have:
Pleasing appearance and feel post application
Non-greasy and rinsable
Creams are good for most topical purpose and considered particularly suited for application to oozing wounds.
Gels or Jellies: Aqueous colloidal suspensions of hydrated forms of insoluble medicament
which are richer in liquid than magma. Jellies are transparent (e.g. water itself) or
translucent (e.g. the polymer is present in colloidal aggregates that disperse light) non-greasy semisolid gels.
Gels or Jellies are used for medication, lubrication and some miscellaneous applications e.g. carrier for spermicidal agents to be used intra vaginal with diaphragms.
Poultices, plasters, foams:
Poultices = soft, viscous, pasty preparations for ext. use that are applied to skin while hot to
supply to inflamed parts of the body e.g. Kaolin Poultice (B.P.C.).
Plasters = are solid semisolid masses which adhere to the skin when spread upon a backing
material (e.g. cotton felt line or muslin) mainly used to:
1. Afford protection and mechanical support
2. Furnish an occlusive and macerating action
3. Bring medication in close contact with the surface of the skin
Foams = are system in which air or some other gas is emulsion in liquid phase to the point of stiffening. E.g. shaving creams, whipped creams, aerosolized shaving creams.
Semi-Solid Properties:
1. Physical Properties
a. Smooth Texture
b. Elegant Appearance
c. Non Dehydrating
d. Non Gritty and Non Hygroscopic
e. Non Greasy and Non Staining
2. Physiological Properties
a. Non Irritating
b. Do not alter membrane/ skin functioning
c. Miscible with skin secretion
d. Have low sensitization index
3. Application Properties and Storage Properties
a. High aqueous washability
b. Storage temperature not exceeding 25 degrees centigrade unless otherwise authorized and not allowed to freeze
c. Storage container: well closed container or airtight container
d. Containers: Preferably collapsible metal tubes from which the preparation may be readily extruded.
“Manufacturing of Creams, Ointments and Other Semi-Solid Preparations”
Semi-solid preparations may be susceptible to microbial and other contamination during its preparations thus special measures have to be taken to avoid products from being contaminated. Control points include:
a. Personnel e. Equipments
b. Clothing f. Sterilization Process
c. Building and Air Handling g. Water
d. Cleanliness and Hygiene g. Processing/ Production
Premises and Equipment
1. The use of closed systems of processing and transfer is recommended to protect from contamination.
a. Production areas where the products or open clean containers are exposed should normally be effectively ventilated with filtered air.
i. Use HEPA filter (99.95%) for incoming air into the processing and filling or filling under laminar air flow is encouraged.
b. Production areas should never be used for other activities
2. Tanks, containers, pipe works and pumps should be designed and installed that they maybe cleaned and if necessary sanitized.
a. In particular, equipment design should include a minimum of dead legs or sites where residues can accumulate and promote microbial proliferation.
i. To prevent dead legs, outlets from circulation pipes should not be longer than 6 pipe dm including valves.
ii. Diaphragm valves and not ball valves are preffered, particularly at sampling points.
3. All equipment which have direct contact with the production should be disinfected or sterilized before use either with the use of:
a. Chemicals e.g. 70% ethanol; 70% IPA; 3% Hydrogen Peroxide
b. Dry Heat or Moist Sterilization
c. Gamma Ray Radiation
d. Ethylene Oxide
4. The use of glass apparatus should be avoided wherever possible.
a. High quality stainless steel is often the material of choice for parts which come in contact with the product.
b. If glass equipment is used, it must be checked for damage before and after use.
c. Dipsticks should be made from stainless steel or other inert material and not glass (easily broken) and
i. Calibrated for each container
ii. Should be used for 1 container only
5. Measures to reduce the risk of contamination must be taken:
a. Dedicated garments and hair covers
b. Where local procedures are used, it is recommended that there is local air filtration and gloves are worn
c. Prompt cleaning of used equipment
d. Rinsing equipment that contact the production with an appropriate grade of water washing (e.g. freshly prepared purified water or boiled water for injection or irrigation)
e. Checking of residues of non-volatile sanitizing agents are used (e.g. hypochlorite)
f. Check if equipment is clean and dry before being stored
g. Careful storage of cleaned equipment
h. All materials brought into the production area must be clean
i. Sanitizing critical surfaces with alcohol
j. Final production containers should not be reused
k. Mops and cloth should not shed fibers, sanitized each day if these are reused and are not used to clean other areas
l. If more than 1 activity is undertaken in the production area at a time there should be adequate segregation to prevent cross-contamination and mix-ups. A risk analysis should be performed.
m. The use of dedicated equipment is recommended for potent substance (cytotoxic, ectoparaciticides & other substances) that are very hazardous & difficult to clean.
“Production of Semisolid Preparations”
1. The chemical and microbiological quality of water used in production should be specified, monitored & results periodically recorded and documented (typically weekly).
a. It must comply with the pharmacopoeial requirements: e.g. For routing monitoring: bioburden (total viable aerobic cnt.); conductivity; total organic carbon (TOC) or other comparable readings. Purified water is highly recommended to contain a maximum of 100 col. per mL and should not contain pathogenic microorganism, e.g. coliform, salmonella, and pseudomonas aeruginosa and staphylococcus aureus.
b. Specific chemical analysis should be performed occasionally (typically 3 months).
i. If appropriately certified, there is no need to conduct chemical and microbiological analysis, where sterile bottled water for injection is used.
ii. After any chemical sanitation of the water systems, a validated flushing procedure should be followed to ensure that the sanitizing agent has been effectively removed.
iii. Care should be taken in the maintenance of water systems in order to avoid the risk of microbial proliferation.
iv. It is recommended to boil the water before use or sterilized by filtration sing membrane filter to pore size 0.2 micron.
2. The quality of materials received in bulk tankers should be checked before they are transferred to bulk storage tanks.
3. Materials likely to shed fibers or other contaminants, e.g. cardboard or wooden pallets should not enter the areas where products or clean containers are exposed.
4. Care should be taken to maintain the homogeneity of mixtures, suspensions, etc. during filling.
a. Mixing and filling processes may require validation and mixing times and speed must be recorded
b. Special care should be taken at the beginning of the filing process, after stoppages and at the end of the process to ensure that homogeneity is maintained.
5. Care should be taken when transferring materials via pipelines to ensure they are delivered to their correct destination.
a. Color coding of pipelines with proper identification.
6. When the finished product is not immediately packaged, the maximum period of storage conditions should be specified and respected.
7. Samples of the finished product must be visually examined before release.
8. Expiry dates (use by dates) must be set and justified for the unopened products. Once the container is opened, it may be necessary to recommend an application date.
“Steps involved in Semisolid Manufacture”
1. Preparation of aqueous phase
2. Preparation of oily phase
3. Preparation of active ingredients solution
4. Mixing aqueous phase with oily phase and active ingredient solution
5. emulsification, cooling and homogenization
“Operating Principles and Equipments in the preparation of Semisolid”
1. Particle Size Reduction: The mechanical process of breaking particles into small pieces via 1 or more size reduction mechanism. The mechanical process used is generally referred as Milling.
a. Particle Size Reduction Mechanisms
i. Impact – by applying instantaneous force perpendicular to the particle and
or agglomerate surface.
ii. Attrition – particle size reduction by applying force parallel to the particle surface
iii. Compression – particle size reduction by applying force slowly (as compared to impact) to the particle surface
iv. Cutting – particle size reduction by applying a shearing to material
b. Equipment
i. Fluid energy Mills v. Screening Mill
ii. Separators vi. Cutting Mill
iii. Compression Mills vii. Tumbling Mill
iv. Impact Mills
2. Particle Size Separation: Particle size classification according to particle size alone.
3. Mixing: The reorientation of particles relative to 1 another to achieve uniformity or
Randomness. Heating and Cooling via indirect conduction maybe used to facilitate phase mixing or stabilization.
a. Mixing Process includes:
i. Wetting of solids by a liquid phase
ii. Dispersion of discrete particles
iii. Deagglomeration into a continuous phase
b. Mixing Equipments:
i. Convection mixers, low shear
ii. Roller mixers
iii. Convection mixers, high shear
iv. Static mixers
4. Emulsification: The application of physical energy consisting of at least 2 immiscible phases, causing 1 phase to be dispersed into the other.
a. Equipment Used:
i. Low Shear Emulsifier – (mechanical stirrer or impeller) can differ in the type of fluid flow imparted to the mixture (axial flow propellers or radial flow turbines)
ii. High Shear Emulsifier – differ in the method used (dispersator, roto stator, valve or pressure homogenizer)
5. Deaeration: The elimination of trapped gasses to provide more accurate volumetric measurement and remove potentially reactive gases. This can be done by the use of vacuum or negative pressure; alone or in combination with mechanical intervention or assistance.
a. Equipment Used: Deaerators (offline or in line, vacuum vessel)
6. Transfer: The controlled movement or transfer of materials from one location to another.
a. Operating Principle: (Active or Passive)
i. Active = The movement of material across a mechanically induced pressure
gradient usually thru conduit or pipe.
ii. Passive = The movement of material against a mechanically induced
pressure gradient usually thru conduit or pipe.
b. Equipment Used:
i. Low Shear = active or passive material transfer with a low degree of induced shear (e.g. diaphragm, gravity, peristaltic, piston, pneumatic)
ii. High Shear = active or passive material transfer with a high degree of induced shear (e.g. entrifugal or turbine, piston, rotating gear)
7. Packaging:
a. Holding = The storage of product material in a vessel that may or may not have
temperature control and agitation.
b. Transfer = The controlled movement or transfer of material from 1 location to another
c. Filling = Pre-cleaning of the primary package to remove particulates by the use of
ionized air, vacuum or inversion. The actual filling into primary containers can involve a metering system on gear, orifices, peristaltic or piston pump.
d. Sealing = Thru conducted heat or electromagnetic (induction or microwave)or by
mechanical manipulation (crimping or torquing).
e. Equipment Used:
i. Holders (auger, gravity, pneumatic nitrogen)
ii. Fillers (auger, gear pump, orifice, peristaltic pump, piston)
iii. Sealer (heat, induction, microwave, crimping, torque)
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