Organization and Personnel in Pharmaceutical Manufacturing

Organization

A social unit structured to meet needs or pursue goals.
Management structure defines relationships and assigns roles.

Personnel

Involved in processing, manufacturing, packaging, and control of drug products.
Must have sufficient knowledge, training, and experience.

Organization Organogram

General Manager oversees various departments.
Departments include Sales, Operations, Purchasing, and Quality Control.
Roles include Sales Representatives, Production Supervisors, Quality Control Inspectors, and Department Planning.

Types of Personnel

Research: Teamwork and understanding of each other's problems are crucial.
Production: Coordinate manpower, materials, and machinery for maximum quality output.
Quality Control: Capacity to work meticulously with precision.
Marketing: Good communication skills, personality, and convincing ability are essential.

Personnel Qualifications

Required education, training, and experience to perform assigned functions.
Adequate number of qualified personnel for all stages of drug product handling.

Personnel Responsibilities

Wear clean clothing appropriate for duties.
Use protective apparel to prevent drug product contamination.
Practice good sanitation and health habits.
Limited-access areas restricted to authorized personnel.

Responsibilities of the Head of Production

Ensure products are produced and stored according to documentation for required quality.
Approve production operation instructions and ensure strict implementation.
Evaluate and sign production records.
Ensure department, premises, and equipment maintenance.
Perform and record process validations and equipment calibrations.
Ensure initial and continuing training of production personnel.

Responsibilities of the Head of Quality Control Department

Approve or reject materials based on specifications.
Evaluate batch records.
Ensure necessary testing is carried out.
Approve sampling instructions, test methods, and quality control procedures.
Approve and monitor analysis carried out under contract.
Check department, premises, and equipment maintenance.
Ensure validations and calibrations of control equipment.
Ensure initial and continuing training of quality control personnel.

Responsibilities of QA Department

Compliance with Regulations: Monitor and adhere to GMP and other standards.
Documentation Review: Approve manufacturing and batch records, SOPs for accuracy and compliance.
Audits and Inspections: Conduct internal and external audits to identify quality issues.
Change Control: Manage and approve changes to minimize risks and maintain quality.
Product Quality Reviews: Assess finished products and implement corrective actions.
Validation and Qualification: Oversee equipment and process validation.
Training and Awareness: Provide training on quality standards and regulatory compliance.

Training

Acquisition of technology to perform jobs to standards.
Training for personnel in production, control laboratories, and maintenance.

Objectives of Training

Awareness of cGMP concepts.
Generate high performance through employee and management contribution.
Manage a safe and healthy environment.
Demonstrate cleanliness, hygiene, and personnel health.
Demonstrate handling and storage of drug products.
Ensure the use of safety measures in emergencies.

Types of Training

Induction Programme: Familiarize new employees with the work environment.
On Job Training (OJT): Carried out after induction training, department head responsible for conducting and evaluating.
Class Room Training (CRT): Annual training calendar with topics from various departments.
Outside training: Training for new equipment or instruments at external facilities.

Validation of Training

Assurance that training meets expected standards.
Certification process for skills and knowledge.

Evaluation

Evaluated by question papers after completion of each training.
Retraining if trainee does not qualify.

Personal Hygiene

Safeguard product quality and avoid contamination.
Individual responsibility for product quality.
Detailed hygiene programs adapted to factory needs.
Procedures relating to health, hygiene practices, and clothing.
Prohibition of eating, drinking, chewing, smoking, or storing related materials in production and storage areas.
Personnel instructed to use hand-washing facilities.

Personal Records

Minimum health requirements in writing.
Pre-employment medical examination including eye-testing.
Periodic health check-ups for all personnel.
Special attention to communicable diseases.
Medical certificate after medical leave.
Reporting of infectious diseases.
SOP on penicillin sensitivity test.

Premises Design, Construction, and Plant Layout

Suitable size, construction, and location to facilitate operations.
Situated to avoid contamination from external environment.

Design & Construction

Designed and maintained to suit manufacturing under hygienic conditions.
Compatible with manufacturing operations.
Adequate space for equipment and staff movement.
HVAC system for environmental monitoring.
Proper drainage and waste disposal system.
Walls and floors free from cracks, smooth and washable.
Regular cleaning and disinfection.
Appropriate electric supply, lighting, temperature, humidity, and ventilation.

Plant Layout Objectives

Streamline flow of materials.
Minimize material handling.
Effective utilization of resources.
Minimize product adulteration.
Optimize space utilization.
Provide clear access routes.
Design for easy cleaning and sanitation.
Implement proper ventilation and environmental control.
Reduce waste.

Principles of Plant Layout

Minimum Movement: Minimize transportation and material handling.
Space Utilization: Effective use of cubic space.
Flexibility: Adaptable to changes.
Interdependence: Close proximity for related operations.
Overall Integration: Integration of facilities and services.
Safety: In-built provision for worker comfort and safety.
Smooth Flow: Reduce bottlenecks and facilitate uninterrupted work flow.
Economy: Aim at economy in fixed assets.
Supervision: Facilitate effective supervision.
Satisfaction: Boost employee morale.

Types of Plant Layout

Product Layout (Line Layout): Machines arranged in sequence for specific product.
- Advantages:
  - Reduced material handling cost.
  - Perfect line balancing.
  - Short manufacturing cycle.
  - Simplified planning and control.
  - Small work-in-progress inventory.
  - Lesser wage cost.
- Disadvantages:
  - Lack of flexibility.
  - Large capital investment.
  - Dependence on each part.
  - Duplication of machines.
  - Costly maintenance.
- Suitability:
  - Standardized products, large volumes, time and motion studies, good labor and equipment balance.
Process Layout (Functional Layout): Machines grouped by similar operations.
- Advantages:
  - Greater flexibility.
  - Lower investment.
  - Higher utilization of production facilities.
  - Variety of jobs.
  - Breakdown doesn't stop work.
- Disadvantages:
  - Backtracking and long movements.
  - Higher material handling costs.
  - Difficult planning and control.
  - More space required.
  - Difficult to trace responsibility.
- Suitability:
  - Non-standardized products, special orders, difficult to achieve balance, production not on a large scale.
Fixed Position Layout: Manufacturing operations occur in a single area, workers and equipment move around the product.
- Advantages
  - Lower costs
  - Reduced material movement
  - Simpler customization
  - Less product damage
- Disadvantages
  - High variable costs
  - Increased equipment movement
  - Space utilization

Factors Influencing Plant Layout

Product type: Standardized, customized, or complex manufacturing.
Production volume: High or low volume production.
Location: Site size and terrain.
Manufacturing process: Continuous flow, batch, or job-shop.
Material handling: Minimizing movement and storage.
Labor requirements: Number of workers and skill levels.
Management policies: Quality control, flexibility, and environmental considerations.

Maintenance

Proper keeping and repair of equipment and facilities.
Objectives:
- Keep plant items fit at lowest cost.
- Minimize accidents.
- Maximize useful life of equipment.
- Minimize wear and tear.
- Reduce major overhauls.
- Improve profitability and productivity.
Benefits:
- Good productivity.
- Valuable information regarding equipment life.
- Safe working conditions.

Types of Maintenance

Planned Maintenance
- Preventive Maintenance
  - Running
  - Scheduled
  - Shut down
- Corrective Maintenance
- Predictive Maintenance
Unplanned Maintenance
- Emergency

Planned Maintenance

Carried out with forethought, planning, record keeping, and control.

Preventive Maintenance

Principle: Prevention is better than cure.
- Reduce wear and tear and ensure smooth running.
- Inspection, Cleanliness, Lubrication, and Routine repairs.
- Anticipation of failure and preventive action.
Types:
- Running maintenance: Performed while the item is in service, e.g., lubrication.
- Scheduled maintenance: Aimed at avoiding breakdowns, e.g., overhauling.
- Shut down maintenance: Performed during shutdown, medium frequency.

Corrective Maintenance

Performed to restore a failed unit, including adjustment or redesign.
Types:
- Breakdown maintenance
- Shutdown maintenance

Breakdown Maintenance

System taken out of production for repairs. Economically justified if preventing failure is more costly.

Predictive Maintenance

Predict time of failure and extent of breakdown.
PDCA cycle (Plan Do Check Act).

Unplanned Maintenance

Carried out without forethought or planning, tool of crisis management.

Emergency Maintenance

Implemented immediately to avoid serious consequences, e.g., gas leakage, fire hazards.

Sanitation

Clean and sanitary conditions for buildings and premises.
Free of rodents, birds, insects, and other vermin.
Written procedures for cleaning schedules, methods, equipment, and materials.
Written procedures for use of rodenticides, insecticides, and cleaning agents.
Procedures designed to prevent contamination.
Sanitation procedures apply to all employees, including contractors.
SOPs available for external areas.
Cleaning of areas and equipment, microbial monitoring, and disinfection.

Environmental Control for Sterile Products

High degree of precaution and prevention.
Strict compliance with standards.
Sterile areas/ aseptic processing areas should have:

Control of Contamination in Sterile Areas

Two main Sources of Contamination:
- Area/Facilities
- People.
Areas/Facilities
- Air should be supplied under positive differential pressure with HEPA filters designed to keep Microorganisms and other particles at low level
- In sterile areas all the surfaces of floors, walls, ceilings etc should be hard and free from cracks to avoid dust and microorganism accumulation and should permit easy cleaning
- Access to sterile areas must be Controlled/ Restricted to people and entry and exit to sterile areas should be only permitted through change areas
People
- Follow the written changing and wash-up procedures
- Avoid coughing and sneezing (If it is unavoidable, please leave the sterile area)

Control of contamination by cleaning and disinfection

There are various points regarding cleaning and disinfection that are mentioned, should be followed exactly and strictly.

Utilities and Maintenance of Sterile Area - Floors , walls & ceilings

Floors ,walls & ceilings must be smooth, easy to clean & disinfected.
Flexing & non-flexing material are used for construction of floor.
Walls must be made from fire-resistant material like stainless steel, glass.
For reduction of fungal growth 1% of 8-hydroxyquinoline, pentachlorophenol may be added to the paints.
Epoxy resin paints and polyurethane paints are used to avoid cracking and peeling.
Cupboards, drawers, shelves must be kept to minimum.

Doors, windows and services

Doors & windows should fit flush with the walls.
Windows if required, are solely to provide illumination and are not for ventilation. Windows should be non-openable.
Doors must be fitted by maintaining positive pressure air flow and self-closing. Must be limited in numbers.* All pipes passing through the walls of room should be effectively sealed and should be easily cleaned.
Gas cylinders should be avoided & all gases should be piped from outside the area.
Sinks & drains must be excluded.
Light sources in rooms are fitted with the ceilings to reduce collection of dust & to avoid the disturbance to the airflow pattern.
Non-essential switches like light switch should be install outside the room.

Personnel & Protective Clothing

Personnel selected to work on the preparation of parenteral products must be neat & reliable.
Should have good health & free from dermatological problems.
No. of operators should be minimum.
Operator should wear sterile protective clothing including headwear, plastic gloves, a non-fibre shedding facemask and footwear.
Fresh sterile clothing should normally be provided each time the person enters the aseptic area.

Cleaning & Disinfection

Cleaning agents are alkaline detergents, non-ionic and ionic surfactants.
Different types of disinfectants should be used in rotation to prevent the development of resistant strains of microbes.
Sodium hypochlorite, ethanol and formaldehyde solutions are used as disinfectant in cleaning area.
Cetrimide / chlorhexidine in 70% alcohol is suitable to use as skin disinfectant.
Air supply
Air supplied to clean room must be filtered through HEPA filters. And it is 99.97% free from microbes.
The HEPA filter must be positioned at the inlet of clean room and the prefilter may be fitted upstream of the HEPA filters to increase the life of the final filter.

Equipment & Raw Material

Equipment may be defined as any piece of plant, machinery, instrument etc. which is used for carrying out a specific activity or operation.
All the manufacturing process or control activities depend upon the good performance of the equipment.
Equipments may be - single system or piece, or integrated system.
The pharmaceutical industry makes use of different equipment at each stage of the manufacturing of drug products.

SELECTION OF EQUIPMENT

Selection of equipment has both strategic and financial impact on the companies.
It has an essential for any company because it has direct influence on the success of the product facilities by optimum cost, improving quality, safety, and reducing environmental hazards.
Selection of an equipment therefore depends on the following factors :-
- Operating criteria
- Availability of spares and servicing
- Maintenance
- Environmental issues
- Availability of designs and maintenance manuals
- Cost

PURCHASE SPECIFICATION OF EQUIPMENT

Some of the important purchase specifications that should be considered are:-
- Desired output capacity - equipment purchased must be capable of processing desired quantity of product at the desired speed of operation.
- Product characteristics – the nature of the product, its reactivity, any special conditions necessary to ensure retention of its safety, efficacy and quality are all important
- Ease of operation - equipment operation must be simple, and not involve complex skills. The equipment must be easy for the operator to operate after receiving proper training.
- Ease of cleaning & maintenance - equipment will require cleaning and special, more thorough cleaning between batches of different products. The time used for cleaning is the time loss from manufacturing. So equipment must be easy to clean and maintain.
- Equipment supplier - price is often considered as an important criteria, but it is also important to consider quality before purchase of an equipment. Also the reputation of supplier should be considered

Purchase specifications:

Before we take decision to purchase an equipment we need to look many aspects.
This primarily helps the user requirement specification for the equipment.
Following questions may arise in relation to design, size, location, adaption and construction of the equipment.
- Why the need arises for the purchase of equipment
- Which operations we want perform with proposed equipment.
- What capacity the equipment should have in terms output and holding?
- How the equipment will be cleaned?
- Do we have trained operators to operate this equipment?
- What will be the starting and stopping time of the equipment?

Cleaning

Cleaning is removal of residues & contaminants from previous utilized equipment
Inadequate cleaning- may result into malfunction or breakdown with adverse effects on products
Cleaned, stored, sterilized, sanitized to prevent contamination as the case may be
Methods of cleaning- documented, how, when, where of performing operation, personnel responsible, cleaning agents

Equipment cleaning procedure

Sufficient details of cleaning each type of equipments
Cleaning procedures:
Details of assigned responsibilities
Cleaning schedules with sanitizing schedules if
Complete methods, materials, dilution of cleaning agents
Instructions for disassembling & reassembling of equipments for cleaning
Instructions for removal of previous batch identification
Instructions for protection of clean equipments from contamination prior to use
Inspection of equipments for cleanliness immediately
before use
Written procedures for cleaning & its release for use
Acceptance criteria for residues & choice of cleaning
procedures & agents must be justified

Equipment cleaning records:

Records of cleaning for major equipments must be maintained
Non major equipments: scoops, ladles, stirrers, spatulas cleaned properly
Log books for each piece of equipment, not dedicated to manufacture of single product

MAINTENANCE OF EQUIPMENT

Equipment maintenance is defined as facilities maintain to some desired level of efficiency to keep assets in a satisfactory condition.
Types of equipment maintenance:-
- MAINTENANCE
  - BREAKDOWN MAINTENANCE
  - PREVENTIVE MAINTENANCE
  - MAINTENANCE PREVENTION
  - CORRECTIVE MAINTENANCE
  - PERIODIC MAINTENANACE
  - PREDICTIVE MAINTENANACE
BREAKDOWN MAINTENANCE:- means that people waits until equipment fails and repair it. Such a thing could be used when the equipment failure does not significantly affect the operation or generate any significant loss.
CORRECTIVE MAINTENANCE:- improves equipment and its components so that the preventive maintenance can be carried out reliably. Equipment with design weakness must be redesigned to improve reliability.
MAINTENANCE PREVENTION:- indicates the design of a new equipment. Weakness of current machines are sufficiently studied and are incorporated before commissioning a new equipment.
PREVENTIVE MAINTENANCE:- is daily maintenance, design to retain the healthy condition of equipment and prevent failure through the prevention of deterioration, periodic inspection or equipment diagnosis, to measure deterioration. It is further divided into :-
Periodic maintenance - time based maintenance consists of periodically inspecting, servicing and cleaning equipment and replacing parts to prevent sudden failure and process problems.
Predictive maintenance - is a method in which the service life of the important is predicted based on inspection or diagnosis, in order to use the parts to the limit of their service life.

WHAT ARE RAW MATERIALS?

All materials that are used into the
manufacturing of a finished bulk (even though it
may not be present in final product) and which are
consumed by person using it are called as raw
material.
Raw materials can be either active drug or
inactive substance.

PURCHASE SPECIFICATION OF RAW MATERIALS

Written guidelines that precisely define the operational, physical, and /or chemical characteristics, as well as the quality and quantity of a particular item to be required.
Regarding purchasing of pharmaceutical materials following points should be considered:-
- All materials should be purchased against an approved and
adequate specification which defines not only the grade and
quality of the materials, but also the nature of the packaging
and container used.
- The quality material should clearly specify the physical,
chemical, and microbiological specifications as specified in
pharmacopoeial or in-house specifications.
- The quality parameters should also specify characteristics like, bulk density, particle size etc.
- Material should be purchased and sourced only from approved suppliers and manufacturers.
- Choice of vendor should be primarily based on quality considerations and when these are met other commercial considerations should play their role, like, price, delivery period.
- Consistency in quality, delivery and price should be given importance
- Raw and packing materials should only be purchased by buyers who are trained and poses sufficient technical knowledge.

STEPS OF PURCHASING RAW MATERIALS

Purchase Requisition
Selection of Vendors
Inviting Quotation
Placing the Order
Receiving Materials
Sampling and Testing of Incoming Materials
Checking of Invoice/Bill,
Recording of Bill in Books
Releasing the payment to the Supplier

SELECTION OF VENDORS

Selection of vendors is carried out in 4 stages:-
- First stage survey stage - identify potential sources through trade directories, web browsing, trade journals, supplier's catalogue etc.
- Second stage enquiry stage analysis of information in standard enquiry format. Enquiry stage is done to ensure internal facilities of vendors, financial adequacy and stability, reputation of vendor, location of vendor's factory and industrial relations.
- Third stage - negotiation and selection stage-quality control specifications, clarification, credit, quantity discounts.
- Fourth stage experience and evaluation stage the buyer evaluates and appraises the performance of the vendor. The objective is to improve the performance of vendors in which they are deficient. Evaluation is done especially on two counts - quality and delivery.

RECEIVING MATERIALS

Visual examination for all incoming materials, containers, lids and seals.
Check for physical damage to the containers, rodent or insect infestation, proper labelling in specified manner.
Materials should be quarantined until they have been sampled, examined, and released for use.
Before incoming materials are mixed with existing stocks, they should be identified as correct, tested and released.

SAMPLING AND TESTING OF INCOMING MATERIALS

At least one test to verify the identity of each batch of material should be conducted.
A suppliers certificate of analysis can be used in place of performing the tests. Provided manufacturer should evaluate the suppliers.
Supplier approval should include an evaluation that provides adequate evidence that the manufacturer can consistently provide material meeting specifications.
Samples should be representative of the batch of material from which they are taken.
Sampling methods should specify the number of containers to be sampled and the amount of material to be taken from each container.
Sampling should be conducted at defined locations and by procedures designed to prevent contamination of material sampled.
Containers from which samples are taken should be opened and reclosed carefully.
Cleaned, dried, and sanitized utensils should be used for sampling.
Sampling room should have specific temperature, relative humidity, and air pressure.
There should be specific requirements for specialised products like - sterile products, poisons, patent drugs, beta lactum products, hormones, and steroids.
Sampled containers and sample collection containers should have the following details :-
- Name of the material
- Batch no. for manufacture
- Date of Sampling
- Name and sign of Sampler

PURCHASE RECORDS

Points to be checked and recorded:-
- Date of receipt
- Name of the product
- Batch no.
- Control no. assigned by the manufacturer
- Quantity received
- Name of supplier
- Purchase order no.
- Excise gate pass
- Date of manufacture and expiry

MAINTENANCE OF STORE FOR RAW MATERIALS

Materials should be handled and stored in a manner to prevent degradation, contamination, and cross contamination.
Materials stored in fibre drums, bags, or boxes should be stored off the floor
Suitably spaced to permit cleaning and inspection.
Materials should be stored under conditions and for a period that have no adverse affect on their quality
Oldest stock should be used first
Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorised use in manufacturing.

LOCATION OF STORAGE AREA

Stores should be located adjacent to the manufacturing area.
Location depends upon the nature and value of items to be stored and the frequency with which items are received and issued.
Minimum wastage of space, handling costs and operating costs.
Maximum ease of operations.
FACILITIES
- Inspection centre
- Space for storing retained samples for quality control
- Centralised weighing areas
- Washing room
- Quarantine room

STORAGE AREA CONDITIONS

Room temperature - $30°C$
Relative humidity - 60%
A.C storage temperature - $25+2 °C$ , RH-55%
Low temperature storage - 2-8 °C
Light sensitive material in amber colour container.

LABELLING OF MATERIAL IN STORAGE AREA

Designated name of product
Batch no given by supplier
Status of content
Expiry date or date beyond which retesting is necessary