Plant Training on Aristopharma Ltd (Part 2)

Liquid Preparation

Liquid Dosage forms are homogeneous preparations containing one or more active ingredients dissolved or suspended in a suitable vehicle.

The liquid section is very essential for any pharmaceutical company to become a good one.

Aristopharma includes the following liquid preparations:-

• Oral Syrup
• Suspension

Figure: Liquid dosage form

General Manufacturing Process of Oral Liquid     

The general manufacturing of oral liquids in the liquid section of Aristopharma Ltd is briefly described below with a flowchart:

 Flowchart of manufacturing of oral liquid

Weighing of active ingredient/s along with excipients

Mixing of excipients with certain amount of demineralized (DM) water as specified in the Batch Production Record (BPR) by the aid of a mechanical stirrer

   Addition of active ingredient/s

   Passing through a pump to the storage vessel to the

Transfer of the solution to the filling vessel through 0.5m Cartridge filter.

Filling, Flushing of Nitrogen (N₂) & Sealing of Bottles (glass or pet) containing oral liquids

Oral Syrup

Syrups are sweet viscous aqueous liquids. Pharmaceutically, Syrup are those which are concentrated solutions of a sugar and those which are formulated with artificial sweetening agents and viscosity builders.

Steps of syrup preparation

        Prepartion of syruo solution with sucrose

          Transfer to compounding vessels

      Addition of active materials & other ingredient

              Mixing with continuous stirring

       Adjustment of final volume with DM water

                      Filtration of Liquid

                          Filling & sealing

                       Checking of clarity

                         Online packaging

Important parameters of syrup preparation

Excessive heating in the preparation of syrups must be avoided to prevent inversion of sucrose, with increased tendency to fermentation.

 The syrup is prepared by adding sucrose to the aqueous solution in a bottle of about twice the size required for the syrup. This permits active agitation and rapid solution.

 The stoppering of the bottle is important, as it prevents contamination and loss during the process.

 Preservatives such as glycerin, methyl paraben, benzoic acid and sodium benzoate may be added to prevent bacterial and mold growth, particularly when the concentration of sucrose in the syrup is low.

 The official syrups should be preserved in well dried bottles and stored in a cool  dark

Place.

Suspension

A pharmaceutical suspension may be defined as a coarse dispersion containing finely divided insoluble materials suspended in a liquid medium or available in dry form to be distributed in the liquid when desired.

 Steps involved in Suspension Preparation

Dispersion of suspending agent

 Transfer to compounding vessel containing sucrose solution

 Addition of drugs & other ingredient

Mixing with continuous stirring

 Adjustment of final volume with purified water

  Filling & sealing

 Packaging

Machines used in the Oral Liquid Manufacturing unit

Condition for manufacturing of Oral Liquids

 Relative Humidity: Not more than 55%.

  Temperature: Below 30⁰

In the packaging unit, filled & sealed bottles are sequentially-

                 → Labeled

                 → Packed with an insert in the intermediate carton

                 → Finally packed in master carton.

 Particulars of in-process Check

– Empty bottle or tube.

– Breaking of the bottle or spot of the tube.

– Incomplete sealing.

– Weight variation test.

– Batch number of the product.

– Leakage of the plastic container.

Semisolid Dosage Forms

Topical delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorders (e.g. acne) or the cutaneous manifestations of a general disease (e.g. psoriasis) with the intent of containing the pharmacological or other effect of the drug to the surface of the skin or within the skin.

Semi-solid formulation in all their diversity dominate the system for topical delivery. Aristo pharma provides the following number of topical preparations:-

1. Cream – 14

2. Ointment- 6

3.Gel- 3

4. Lotion-3

5. Shampoo-1

6. Suppository- Trial product

Cream

Creams consist of medicaments dissolved or suspended in water removable or emollient bases. Creams are classified as water-in-oil or oil-in-water. Therefore, combining immiscible compounds is possible by mechanical agitation or heat.

Steps involved in cream

Ointment

Ointments are semisolid preparation intended for external application to the skin or mucous membranes. Ointments are ideal emollients with good skin penetration and adherence to surfaces

Manufacturing process

                                       Preparation of oil phase I

                                       Preparation of oil phase II

                  Oil phase-I to Oil phase-II in a Steam Jacketed Vessel

                                      Addition of Active Ingredients

                                      Blending by Mechanical Stirrer

                                                   Filling

                                                    Sealing

• Batch size – 60kg or 90 kg
• Tube size –  5gm – 30gm
• 2 tubes – Aluminium tube and Laminated tube
• Holder – 20gm                                

Automatic tube filling and Sealing machine process

There are 12 steps in this process. The steps are given follow –

1. Standing of tube
2. Detect by the sensor
3. Compressed air pressure
4. Dose are filled by Doser nozzle
5. 1^st pressure is given
6. Then 1^st fold is done
7. 2^nd pressure is given
8. Then 2^nd fold is done
9. 3^rd pressure is given
10.  –
11. Ambushed
12. Finally ejected

 Sterile products are dosage forms of therapeutic agents, which are free from viable and bacterial endotoxins. All injectables and infusions are prepared as sterile preparations. Sterile preparations also include ophthalmic and irrigation preparation.

Sterilization

Sterilization is the process of killing or removing bacteria and all other forms of living microorganism’s and their spores from preparation of articles. A product is said to be sterile when it is free from all living microorganisms and passes the sterility tests.

 Different Sterilization Techniques & their uses

 Aseptic area 

An aseptic area is a room or special area within a clean area designed, contracted, serviced and used with the intention of preventing microbial contamination of the product. In order to maintain the sterility of the components and the product during processing, careful attention needs to be given to:

• Environment
• Personnel
• Critical surfaces
• Container /Closure sterilization and transfer procedures
• Maximum holding period of the product before filling into the final container.

Clean room

A controlled environment facility in which all incoming air passes through a filter capable of removing 99.997% of all particles 0.3 mili micron and larger ,called clean room.

Classification of aseptic room

• A –class zone: Filling area under laminar air flow .Particle count of this area must be below 100 particles.
• B-class zone: Other portion of filling room except A –class. Particle count of this zone is usually below 100 particles.
• Buffer zone or C-class zone: It consists of cooling room, sealing room and third change room and is below 10000 particles.

Aseptic clean room preparation

Sterile production room must be maintained as CLASS-100. According to USP, CLASS-100 clean room is defined as the room condition, in which the particle count in the air is NMT 100 per cubic foot for particle of 0.5m or larger than that.

At first De-ionized water is sprayed throughout the room so that the particle present in the air must settle down. Then the wall, ceiling and floor are washed by the solution of combination of ethanol, savlon and distilled water.

After cleaning operation, the production room must be fumigated about 12 hours, with the solution combination of formaldehyde and potassium per manganate in the ratio of 3:1. 500ml formaldehyde and 175mg potassium per manganate for per 41 cubic meter area of an aseptic room.

UV light is also used for the removal of viable microorganism.

Preparation; Filling; and Sealing

Commonly the small volume parenteral or injectable products are filled in-

• Ampoules
• Vials

Generally the products are manufactured by two ways:

                       → Aseptically Sterilized

                       → Terminally Sterilized

Injectable Products in Ampoule

Injectable Products are dispensed in ampoules following the procedure given below-

Ampoule De-boxing

Ampoule washing

Sterilization (in case of aseptically filled ampoules)

Ampoule filling (under laminar air flow)

Ampoule Sealing

Terminal Sterilization

Ampoule Inspection

Sealed Ampoules

Ampoule Inspection

• The white zone detects visually the black particles,
• The black zone detects the white particles.

• The volume is measured visually by taking 4 ampoules at a time in hand

Injectable Products in Vials    

Vial Sorting

Vial Washing

Vial Sterilization

Vial cooling

Powder filling

Rubber capping

Alu-sealing

Labeling

Blistering

Packaging

Ophthalmic Preparation

These are sterile preparations, free from foreign particle, bacteria and bacterial endotoxins, compounded and packaged for administration into eye. For manufacturing of ophthalmic preparations manufacturers need aseptic clean room of CLASS 100.

ARISTOPHARMA LTD. Produces eye drops and eye ointment type ophthalmic preparation.

 Flow chart- Eye drop preparation

 WFI collection Buffering Agent

Preparation of Lyophilized Product

Lyophilization

Lyophilization is a process which extracts the water from foods and other products so that the products remain stable and are easier to store at room temperature (ambiant air temperature).

Lyophilization is carried out using a simple principle of physics called sublimation. Sublimation is the transition of a substance from the solid to the vapour state, without first passing through an intermediate liquid phase. To extract water from products, the process of lyophilization consists of:

1. Freezing the food so that the water in the food become ice;
2. Under a vacuum, sublimating the ice directly into water vapour;
3. Drawing off the water vapour;
4. Once the ice is sublimated, the products are freeze-dried and can be removed from the machine.

Lyophilization process is also known as freeze-drying process.

The freeze-drying process

Typically, the lyophilized product is frozen at a temperature well below the eutectic point. There are four stages in the complete drying process: pretreatment, freezing, primary drying, and secondary drying.

Pretreatment

Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability and/or improve processing), decreasing a high vapor pressure solvent or increasing the surface area Methods of pretreatment include: Freeze concentration, Solution phase concentration, Formulation to Stabilize Reactive Products etc.

Freezing

Freezing is usually done using a freeze-drying machine. In this step, it is important to cool the material below its triple point, the lowest temperature at which the solid and liquid phases of the material can coexist. This ensures that sublimation rather than melting will occur in the following steps. Freezing is done rapidly, in order to lower the material to below its eutectic point quickly, thus avoiding the formation of ice crystals. Usually, the freezing temperatures are between −50 °C and −80 °C. The freezing phase is the most critical in the whole freeze-drying process, because the product can be spoiled if badly done.

Primary drying

During the primary drying phase, the pressure is lowered (to the range of a few millibars), and enough heat is supplied to the material for the water to sublime. In this initial drying phase, about 95% of the water in the material is sublimated. This phase may be slow (can be several days in the industry), because, if too much heat is added, the material’s structure could be altered.

In this phase, pressure is controlled through the application of partial vacuum. Furthermore, a cold condenser chamber and/or condenser plates provide a surface(s) for the water vapor to re-solidify on. Condenser temperatures are typically below −50 °C (−60 °F).

Secondary drying

The secondary drying phase aims to remove unfrozen water molecules, since the ice was removed in the primary drying phase. In this phase, the temperature is raised higher than in the primary drying phase, and can even be above 0 °C, to break any physico-chemical interactions that have formed between the water molecules and the frozen material. After the freeze-drying process is complete, the vacuum is usually broken with an inert gas, such as nitrogen, before the material is sealed.

At the end of the operation, the final residual water content in the product is extremely low, around 1% to 4%.

Filling

Lyophilized products are filled by three stages. One stage has included filling of vials and stoppering on line; another stage included filling of vials, transportation to the lyophilizer and then stoppering; a third stage included the filling of vials, loading in the lyophilizer, and exposure to a portion of the nitrogen flush and then stoppering. Since lyophilizer sterilization and sterilization of the nitrogen system used to backfill require separate validation, media fills should primarily validate the filling, transportation and loading aseptic operations.

Testing of Lyophilized Products

There are several aspects of finished product testing which are of concern to the lyophilized dosage form. These include

• Uniformity of dose
• Moisture and stability testing
• Sterility testing of the product.

The advantages of Lyophilization

• Ease of processing a liquid, which simplifies aseptic handling
• Enhanced stability of a dry powder
• Removal of water without excessive heating of the product
• Enhanced product stability in a dry state
• Rapid and easy dissolution of reconstituted product

Disadvantages of Lyophilization

• Increased handling and processing time
• Need for sterile diluent upon reconstitution
• Cost and complexity of equipment

Metered dose Inhaler

A metered dose inhaler (MDI), also known as an aerosol inhaler or puffer, is a device for delivering medicine directly into the lungs. It consists of a pressurised metal canister containing a solution or suspension of medicine, placed within a plastic case with a mouthpiece. When the canister is pushed down, a valve delivers a measured dose of medicine in a fine mist. This is inhaled into the lungs via the mouthpiece. Using an inhaler delivers your medicine directly into the lungs where it is needed.

It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for the treatment of asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as (cromoglicate or nedocromil).

Component of MDI

Propellants:

One of the most crucial components of a MDI is its propellant. The propellant provides the force to generate the aerosol cloud and is also the medium in which the active component must be suspended or dissolved. Propellants in MDIs typically make up more than 99 % of the delivered dose. As for example hydrocloroflurocarbon.

Packaging

Packaging is the process by which the pharmaceutical products are suitable packed in such way that they should retain their therapeutic effectiveness from the time of their packaging to consume by the consumers.

There are two types of packaging

1. Primary packaging. (Direct contact with the product e.g. PVC)
2. Secondary packaging. (No contact with the product e.g. Carton)

Function of Packaging

• To provide physical protection of the product
• To provide barrier protection of the product
• To increase the acceptability of the product
• To increase the stability of the product
• To minimize the transport/shipping hazards
• To improve patients compliance
• To improve the pharmaceutical elegance by use of special color or contrasting printing.

Material used in packing section

      Aluminum foil

      PVC film

      PVDC film

      Bottle

      Pilfer proof cap

      Label

      Unit carton

      Insert

      Plastic spoon

      Plastic dropper

      Plastic cap

      Stopper

      Shipping carton

Primary Packaging materials

  Aluminum foil

  PVC film

  PVDC film

  Glass bottle

  Ampoule

  Vial

  PET bottle

Secondary Packaging materials

  Printed box

  Insert

  Labels

  Outer

  Printed tape

  Liner

There are two types of Packing

• Blister Packing
• Strip Packing

Blister package

A blister package in excellent form of unit dose packaging .It provides excellent environment protection, coupled with an esthetically pleasing and efficacious appearance. It also provides user functionality in terms of convenience, child resistance and now tampers resistance.

Blister materials are two types

  Tray materials

  Lidding materials

Tray materials

• Materials help to Pocket formation to receive the product in deep drawn pockets.
• Tray materials are polypropylene (PP) polyvinyl chloride (PVC), PVDC (polyvinylidene chloride) etc.

Lidding Material

The lidding materials are those which are sealed onto the support material after the tablets or capsules have been properly fed to the preformed support materials.

Lidding material consists of:

  Support material: Hard Aluminum, Soft Aluminum, Paper Aluminum, Paper-PET-Aluminum.

  A sealing agent: Heat-sealing lacquer on the other side.

The area is situated in the first floor.After compression of tablets and coating (if required) the tablets are packed either in blister pack or in the strip pack.

Flow chart of Blister packing

Machinery used by ARISTOPHARMA LTD

 Steps of the machine

                 1.  Forming film reels

                 2. Forming film preheating

                 3. Pocket forming

                 4. Auto feeding system (option)

                 5. Aluminum foil

                 6. Sealing station

                 7. Coding embossing

                     8. Perforation

            9.  Trimming

                 10. Product

Various problems of Blister pack machine

• Formation of small pocket if forming temperature becomes low.
• Sealing problem may occur if temperature becomes low.
• Off-Pocket formation.
• Back film storage.
• Embossing may cut down if cutting displacement occurs.
• Side leak of Blister strip may occur.

Strip package

A strip package is a form of unit dose packaging which is commonly used for the packing of tablets and capsules.

Striping materials

Polyethylene laminated aluminum foil.

Flow chart of strip packing process

 Engineering department is the service department, it is the heart of any pharmaceutical industry as it maintains and repairs all the electrical and mechanical devices of the factory.

Function of Engineering Department

             The function of this department is divided into following types :

• Maintenance or Utility service
• Process
• Power supply

Engineering Department include three section

1. Water treatment plant
2. Effluent treatment plant
3. HVAC system

Water treatment plant

The plant has its own water supply. Water treatment plant supply four types of water, these are

• Hot water
• Purified water
• DM water
• WFI (water for injection)

Hot water

Flow chart of Water purifying process

Effluent treatment plant (ETP)

Equipments of ETP

1. Activated carbon filter
2. Multi grade filter
3. Primary clarifier
4. Secondary clarifier

• Treated water tank
• Sludge refractor tank
• Sludge drying bed

1. Equalization tank

• Diffuser

Chemical used in ETP Plant

• Polyelectrolyte
• Alum
• Lime

Flow chart of Process of Industrial Dust treatment

HVAC System

HVAC (pronounced as four separate letters) is an acronym that stands for “heating, ventilating and air-conditioning” and generally includes a variety of active mechanical/electrical systems employed to provide thermal control in buildings. Control of the thermal environment is a key objective for virtually all occupied buildings.

A heating system (“H” in HVAC) is designed to add thermal energy to a space or building in order to maintain some selected air temperature that would otherwise not be achieved due to heat flows (heat loss) to the exterior environment. A ventilating system (“V”) is intended to introduce air to or remove air from a space to move air without changing its temperature. Ventilating systems may be used to improve indoor air quality or to improve thermal comfort. A cooling system (“C” is not explicitly included in the HVAC acronym) is designed to remove thermal energy from a space or building to maintain some selected air temperature that would otherwise not be achieved due to heat flows (heat gain) from interior heat sources and the exterior environment. Cooling systems are normally considered as part of the “AC” in HVAC; AC stands for air-conditioning.

 Objectives of HVAC system

• Control air temperature
• Control air humidity
• Control air circulation and
• Control air quality.

Heating

There are many different types of standard heating systems. Such a system contains a boiler, furnace, or heat pump to heat water, steam, or air, all in a central location such as a furnace room in a home or a mechanical room in a large building. The system also contains either ductwork, for forced air systems, or piping to distribute a heated fluid and radiators to transfer this heat to the air.

Ventilating                                    

Ventilating is the process of “changing” or replacing air in any space to control temperature or remove moisture, odors, smoke, heat, dust, airborne bacteria, carbon dioxide, and to replenish oxygen. Ventilation includes both the exchange of air to the outside as well as circulation of air within the building. It is one of the most important factors for maintaining acceptable indoor air quality in buildings. Ventilation is used to remove unpleasant smells and excessive moisture, introduce outside air, to keep interior building air circulating, and to prevent stagnation of

Air conditioning

Air conditioning and refrigeration are provided through the removal of heat. Heat can be removed through radiation, convection, and by heat pump systems through a process called the refrigeration cycle. Refrigeration conduction mediums such as water, air, ice, and chemicals are referred to as refrigerants.

Chilled system

This system is involved in the production of chilled water which supplied through pipe to produce air conditioning system. Asiatic has both compression & absorption type chiller system.

HVAC evolved based on

• Technological discoveries, such as refrigeration, that were quickly adopted for food storage.
• Economic pressures, such as the reduction in ventilation rates after the 1973 energy crisis.
• Computerization and networking, used for sophisticated control of large complex systems serving numerous buildings.
• Medical discoveries, such as the effects of second hand smoke on people, which influenced ventilation methods.

WAREHOUSE SECTION

A warehouse management system, or WMS, is a key part of the supply chain and primarily aims to control the movement and storage of materials within a warehouse and process the associated transactions, including shipping, receiving, put away and picking. The systems also direct and optimize stock put away based on real-time information about the status of bin utilization.

Warehouse of ARISTOPHARMA LTD. includes the following sections:

1        Raw materials store

• Active ingredients
• Excipients

2        Packing and packing material store and

3        Finished product store.

Area of ware house

• Quarantine area
• Approved area

Quarantine area

Incoming raw materials are received here and waited until approved by the QA. Store in-charge is responsible for receiving the raw materials. A balance weights the raw materials.

Conditions in the area

      Temperature:22-25⁰C

      RH:67-75%

Purpose of Quarantine area

1. To receive the material.
2. To store the material before it pass the QC test.
3. To store the material before the decision is taken whether it is passed or rejected.

Approved area

Raw materials, which bear the passed label of QC, are stored in this area.

Purpose of approved area

1. To store the approved material.
2. To store the approved materials in different condition as specified by the manufacturer.

Active room

Here only the approved active materials are stored.

      Temperature: 22-25⁰C

      RH: 67-75%

Cool room

It is important for storing raw material which are-

      Temperature and moisture sensitive.

      Volatile

Conditions:

      Temperature: 8-15⁰C

      RH: 45-60%

Penicillin and some non-penicillin actives, cooling agent and flavoring agent are stored in cool room such as Cephradine, Flucloxacillin sodium compacted, Banana flavor, Raspberry flavor, Opadry blue.

Excipient room

Only Excipients are stored.

      Temperature: 22-25⁰C

      RH: 67-75%

Processing of raw materials

      At first raw materials come into the quarantine area. RM store in-charge make a receiving record. One copy of RR is sent to the QC for sampling the RM.

      Raw materials are sampled by QC from quarantine area within 4 days after receiving the RMs. Every container of actives is is sampled for testing but Excipients are randomly sampled by square root of n+1.

      If the sampled materials passed the QC test they are given passed label and transferred to the approved area within 10 days after giving passed.

      After approving, actives and excipients are stored in active store room, Excipient store room, solvents are in the solvent room.

Availability of written procedures/instructions/Forms for routine works

For raw materials stores

  Receives raw material according to the invoice/challan.

  Takes GRIR from the Q.A department.

  Updates the present status of raw materials.

  Stores all raw materials according to the instruction.

  Supplies raw materials according to the FIFO to the production floor.

  Adjust present stock after dispensing the raw material.

  Find out raw material that requires re-test.

  Find out under safety stock.

For packaging materials store

  Receives packaging materials according to the invoice/challan.

  Takes GRIR from the Q.A. department

  Inputs the batch number.

  Store all the packaging materials according to the storage guide.

  Updates the present status of packaging materials.

  Dispense packaging materials according to the requisition from production area.

  Adjust present stock after dispensing the packaging materials.

  Find out under safety stock.

For finished products store

  Receives finished product according to the delivery token of production area.

  Preserves the packaged product report of Q.A department.

  Prepares transfer note.

  Prepares VAT challan.

  Dispense FP according to FRFO basis.

  Updates the current stock of finished goods.

  Find out under safety stock.

  Maintain the proper storage condition of finished product.

Product Development Department

Product development department is very important dept. in pharmaceutical industry. It deals with development of new drugs and new dosage forms of existing product. This dept. of the pharmaceuticals is stimulating and challenging and is suited especially to pharmacist with strong scientific background.

This section also performs the following duties:

  Establishes specifications for all starting materials, excipients and finished products.

  Establishes proper batch documentation system.

  Identity problems and takes positive action, Concerning with previous marketed   formulation

  Evaluates the old and new products.

  Validates the product formulation.

Functions of Product development Department

      New drug specification

      Experimental batch production (EB)

      Pilot batch production (PB)

      Formulation studies

      Verification of drug compatibility with the formulation Excipients

      Perform extensive stability study on the finished product

      Scale up from laboratory to commercial batch of the products

      Optimization of production process & concurrent process validation

      Development of the most suitable analytical methods to evaluate the finished products and concurrently validate the method

      Preparation of master documents for both manufacturing and analysis

      Studies to determine the best packaging for storage

      To formulate new product

      To enhance the quality of the existing product by bringing changes in formulation

      To perform research studies.

Steps of new product launching

1. Gather product information e.g. source,
2. Pre-formulation study .e.g. compatibility with other excipient,
3. Formulation development New Product Launching
4. Drug administration formalities,
5. Pilot trial and accelerated stability testing are run,
6. Readjustment is done if necessary,
7. Development of Batch manufacturing record (BMR,
8. Batch manufacturing record (BMR) for commercial scale,
9. Three commercial batch manufactured under PD

Pre-formulation study

Pre-formulation study is the study of the chemical and physical properties of the drug components prior to the compounding process of formulation. The purpose of the study is to understand the nature and characteristics of each component and to optimize conditions of dosage form manufacture.

Stages of pre-formulation study

      Physiochemical properties and analytical testing for drugs

      Data supporting the development of dosage forms

      Support for quality control and finished product manufacturing.

Development of Existing Product

Existing products demand research in order to:

• Increasing the quality of the product.
• Prevention of any type of problem existing in the product.
• To save time and cost.
•  Increasing the patient acceptance.

Stability testing of new products

Stability testing is done by two ways.

1. Real time stability testing
2. Accelerated stability testing

Real time stability test

The storage condition is-

• Temperature: 30 ± 2°C
•  Relative humidity: 65 ± 5%

Accelerated stability test

The storage condition is-

• Temperature: 40 ± 2°C
•  Relative humidity: 75 ± 5%

Machinery Used in ARISTOPHARMA LTD. Product development department

Quality Assurance Department

Quality Assurance is a wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It involves all the functions requred to maintain the quality during manufacturing and also the factors that influence the stability during shelf-life.

Quality

According to ISO8402 quality is defined as –

“Total of features and characteristics of a product or service that bears on its ability to satisfy a given need’’

In case of drug product Quality means:

1.      Pure

2.      Safe

3.      Effective

Quality relationships

                                      Quality Management

                                       Quality Assurance

                                                  GMP

                                          Quality Control

In ARISTOPHARMA quality comes first, profit comes to its sequence & that is reflected in its motto:

‘Quality – the unit we count’.

TQM (Total Quality Management) is concerned with the integration of all the efforts in the organization towards Quality improvement, Quality Development and Quality Maintenance to meet full customer satisfaction at economic levels.

                Quality, Q= P/ E

Here,

          P= Performance

          E=Expectation

So the Quality of a product should be such that it delighted the customer’s expectation.

The impact of Total Quality Maintenance (TQM)

– Better employee relation.

– Improved operating procedures.

            – Greater customer satisfaction.

– Increased financial performance.

GOOD MANUFACTURING PRACTICE (GMP)

That part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use.

Some other Key Elements of GMP

• Sanitation and hygiene
• Qualification and validation
• Complaints
• Product recalls
• Contract Production and Analysis
• Self-Inspection and Quality Audits

Quality Assurance (QA)

QA= Product design (Formulation to shelf-life)+ Good Manufacturing Practice (GMP)+ Quality control (testing+assessment)+ Quality.

In ARISTOPHARMA LTD. the Quality Assurance Department (Q.A) performs it function through the following 4 sections:Quality Control –  (a) Physicochemical

                             (b) Microbiological

Quality compliance

 Product Development – (a) Formulation

                                       (b) AnalyticalValidation

Primary Functions of QA

1. Quality Control
2. Analytical testing of products
3. Sampling, inspecting and testing of incoming raw materials
4. Bottles, caps, foils, labels, measures, cartons
5. Active and Non active material control
6.  Packaging and labeling components
7. Physical inspection of product and operations at critical intermediate stages
8. In-process controls
9. Control of product through its distribution

Important parameters

• Strict quality control procedures are maintained at every step starting from sourcing of raw materials to dispatch of finished products.

• The latest WHO approved current Good Manufacturing Practices (cGMP) & current Good Laboratory Practices (cGLP) are followed in every step of operation.

• Written Standard Operating Procedures (SOPs) are maintained for every process, which are being closely monitored to ensure that all concerned personnel are complying with these procedures.
  

Flow chart for quality assurance activity

Receiving of Raw & packaging                                        Attachment of quarantine

Materials by visual inspection                                          Tag of yellow color

Sampling of raw & packaging

Materials for QC analysis

Release / rejection                                                            Attachment of respective

                                                                                          Tag for raw & packaging

                                                                                          Material.

Dispensing of raw & packaging

Material

Checking of cleanliness,

Approval of equipment

&area of manufacturing

In process checking of                                                Smpling of  in process

Some parameters during                                               Product to Q.C.

Compression,filling etc.

                                                  In process checking of

                                                    Packing operation

                                           Transfer of finished product

                                           For distribution after

                                           Collecting the retention sample

                                     Investigation of product complaints,

                                     Product recall returned product from

                                     Market

Quality control (QC)

Quality Control is that part of GMP concerned with sampling, specification & testing, documentation & release procedures which ensure that the necessary & relevant tests are performed & the product is released for use only after ascertaining it’s quality.

Importance of Quality Control

Quality control is very much important in pharmaceutical industry. All the factors which contribute either directly or indirectly to the purity, safety, effectiveness and reliability of the product will be included under the term ‘quality’. To achieve all these characters there is need to undertake quality control.

Quality control ensures that a drug will have the following characteristics:

• Genuine Quality as well as good nature
• Physically and chemically pure
• It contains same amount of ingredients as mentioned on the label
• It must be in such a form that after administration it is effective
• Quality in terms of shelf life/stability
• No toxic impurities
  

The Q.C department performs the following major responsibilities-

• Raw materials analyses to issue passed, reject or quarantine advice for each batch of raw
• Material.
• Assessment of the intermediate products for further processing
• Assessment of bulk products for their release, reprocess, reject etc.
• In- process quality control (IPC).
• Control of laboratory reagents.
• Analysis of complaint samples.
• Preserves retention sample for exp. date + 1 year.

Steps of QC

Raw material analysis

• Appearance.
• Odor
• Identification.
• Average weight.
• Uniformity of weight.
• Disintegration time.
• Melting point.
• Solubility
• Refractive index
• Specific gravity
• Moisture content

Finished product analysis

• Appearance
• Identification
• Average weight of tablet
• Hardness
• Thickness
• Disintegration time
• Frability test
• Dissolution
• Content uniformity
• Chemical assay

Sampling

The objective of sampling and subsequent testing is to provide an effective on the quality of the product or substances being processed.

For excipient, sampling done by the following procedure :

1. Ön+ 1 rule, where n = total number of container.
2. 100% sampling

In Aristopharma 100% sampling is done.

Four things should be consider in sampling:

1. Sampler
2. Sample container
3. Sample tools
4. Sampling label

Routine activities

• Samples raw materials, packaging material and finished products.
• Monitors the products at a fixed interval of time after releasing it.
• Stores retention sample from each batch.
• Stores batch wise full quality control record.
• Assess the packed products to release.
• Handles complains with greatest care.

ARISTOPHARMA’s Quality Control (QC) lab is well equipped with the most modern & sophisticated equipments which are handled by skilled, experienced and Innovative pharmacists, chemists and biologists, who work in close co-ordination with production personnel to ensure safe, reliable, therapeutically active and compatible production of the medicines.

Machinery used in aristopharma ltd. q.c department

MICROBIOLOGY SECTION

  Microbiology section is very much important in pharmaceutical industry. It gives the ensured of a quality product. The microbiology section of QC department in Aristopharma Ltd is a well-decorated and segregated area that includes various microbiological testing of the pharmaceutical  and the components used for its preparation for example:-

1. Test of raw material and packaging materials
2. Test of finished product
3. Environmental monitoring
4. microbial limits testing
5. quantitative and qualitative analysis of antimicrobial activity
6.  sterility testing
7. Detection of pathogens
8. Purified water test

Environmental Monitoring

Personnel

• For each session – gloves is monitored (but not immediately after sanitising!)
• Clean room operators are  regularly validated to demonstrate that they do not contaminate gowns during gowning up (gowning qualification)
• Periodic sampling for other locations on gown

Methods

1. Surface monitoring

–        Product contact surfaces, floors, walls, and equipment are tested on a regular basis

–        Surface monitoring is  performed at conclusion of aseptic processing (to minimise risk of contaminating critical surfaces during production)

2.Active Air Monitoring

a certain volume of air is sampled (volume and location should be meaningful)
instruments are calibrated
 3.    Passive Air Monitoring
Settle plates exposed for 30-60 minutes
Media is capable of growing a range of bacteria and moulds (e.g. Soybean Casein Digest Agar (SCDA)/Trypticase Soy Agar (TSA)
          4.  Water
microbiological quality of water  is very important
It has an extensive, comprehensive water testing programme
Feed water, pre-treatment, reverse osmosis (RO), deionized (DI), purified/highly purified and water for injection (WFI) is tested
Water used for parenterals is tested for pyrogens . limit is not more than 0.25 EU/mL
               
Flow chart of testing procedure of microbiology preparation

Sample collection

Media preparation

Culture preparation

Incubation

Colony count

Identification

Result

Tests of microbiology section

1. Microbiological assay of raw materials and finished products
2. Limit test of liquid preparations for the pathogenic organisms.
3. Endotoxin testing
4. Sterility test
5. Preservative test

Sterility test

Sterility test is a quality control test used as part of product release for product required to be sterile.

• In a Grade A laminar air flow cabinet in a Grade B background it is carried out.
• Air supply through HEPA filters, pressures should be monitored and alarmed
• Access to area should be through airlocks
• Soybean Casein Digest medium (SCD), (also knows as Trypticase Soy Broth(TSB)) and Fluid Thioglycollate medium (FTM) is usually used (to detect aerobic and anaerobic organisms)
• At least 14 days incubation
• 20-25°C for SCD/TSB, 30-35°C for FTM
• Caso broth, Thioglycollate broth, Membrane filter, rinse fluid etc. are used to perform sterility test.

Endotoxin Testing

• Parenteral products should be free from endotoxin
• Endotoxin is a lipopolysaccharide present in the cell wall of gram negative bacteria which can cause fever if introduced into the body
• Raw materials, WFI used in manufacture and some finished product is tested for endotoxin
• LAL (Limulus Amebocyte Lysate) test is used for detecting endotoxin (previously a rabbit test) based on clotting reaction of horseshoe crab blood to endotoxin .
• 3 hour incubation for Lal test
• Types of LAL test – Gel Clot, Turbidimetric , Colorimetric

 Limit test

The Microbial Limit Tests are designed to perform the qualitative and quantitative estimations of specific viable microorganisms present in samples.

• It includes tests for total viable count (bacteria and fungi) and Escherichia coli.
• Incubation time 3-5 days
• Limits for liquid Aerobic bacteria- 200CFU, fungus- 26 CFU,
• Limits for cream ointment- niot more than 200CFU
• Lactulose, aerobic microbial count- less than 100CFU

Preservative test

Preservatives are antimicrobials put into products to kill or prevent the growth of microorganisms over a relatively long period of time. Incubation time is 28 days. The typical microorganisms used for preservative challenge studies follow:

• Pseudomonas aeruginosa: Gram-negative
• Escherichia coli: Gram-negative bacterium,
• Staphylococcus aureus: Gram-positive bacterium,
• Candida albicans: Fungus (yeast),
• Aspergillus niger: Fungus (mold),

Machinery Used in Microbiology Lab                                                                              

Media used in microbiology lab

            – Caso agar.

            – Macconkey agar.

            – Vogel gonson (selective media).

            – Catrimide.

            – Lactose broth.

            – Peptone buffer solution (PBF)

           – . Trypticase Soy Broth(TSB)

Bioassay

Antibiotic media no 01 and antibiotic media no 11 are used for bioassay.

Buffer solution

            – Potassium dihydrogen orthophosphate.

            – Dipotassium hydrogen orthophosphate.

            – Disodium hydrogen orthophosphate.

QUALITY COMPLIANCE

The quality compliance experts play a decisive role in (IPQC) in process check to bring imaginative, oriented and innovative approach. They monitor all packaging and starting materials, manufacturing operations to ensure the quality stability of the drugs. 

Major duties and responsibilities

–          Inspection and reporting that manufacturing operations are running as per SOP.

–          IPC of the bulk products.

–          IPC of the finished products

–          Audit

–          Checking general cleanliness

–          Checking that manufacturing instructions and packing instructions of followed properly.

–          Analysis of product, raw materials and water

–          Identification constraints of existing manufacturing and testing operations in compliance with cGMP and find out the possible solution

–          Prepare the compliance related reports/inquires

–          Generation or revision of SOP

–          Coordinating and participating in cGMP, GLP and other training programs that focus on the elements of the compliance program thus striving to ensure that all appropriate employees are knowledgeable of WHO, cGMP standard, local and other regulatory norm.

Documentation

–          The site quality policy manual

–          Reports on general cleanliness

–          Training record

–          Stability study records

–          IPC records

–          Instrument requisition record

–          SOR/Protocol record

–          Training materials

–          Maintains the follows of reports

–          Minutes of meeting

–          Inter-departmental correspondence

–          ISO/cGMP audit circular files

–          The modification the record of MI, PI,CI.

–          The customer complain handling documents

Retention Sample Management

• Sampling of raw materials (Both actives & excipients) & packaging   materials.
• Destruction of rejected or expired Products according to SOP.

Market complain Handling

• Collection of rejected goods & maintenance for at least 5years
• Problematic product handling

IPQC Tests

IPQC means In Process Quality Check. We have observed various tests carried out by compliance personnel. Each of the department in Aristopharma has separate IPQC sector.

Solid department IPQC Test

• Physical appearance.
• Weight variation
• Disintegration time (DT).
• Friability, hardness, thickness test
• Mottling problem.
• Empty shell of capsule.
• Broken and spotted capsule.
• Ensure proper HVAC systems.
  • LOD
  • Leak test
  • Sanitation reports
  • Physical parameter of cartons.
  • Printing, batch no, Mfg. date, exp. date, price etc.

Liquid department IPQC Test

• Volume checks in liquid filling.
• Empty bottle or tube.
• Breaking of the bottle or spot of the tube.
• Incomplete sealing.
• Weight variation test.
• Batch number of the product.
• Leakage of the plastic container.   

Microbiology department IPQC Test

• Weight and volume check of product.
• Cleanliness of production area.
• Confirmation test for selective pathogens.
• Particulate matter counting in aseptic area.
• Sterility test of injectables.

Sterile department IPQC Test

• Before aseptic filtration check the final filter integrity.
• Empty/filled ampoule checking.
• Temperature
• Quantity of filled ampoules (pcs).
• Empty vial washing and sterilization check.
• Vial filling & sealing.

Thus compliance Monitor cGMP to ensure that products are consistently produced and controlled to the quality standard appropriate to the product specification.

Validation

Validation is defined as establishing document evidence, which provide a high degree of assurance that a specific process or system will consistently produce a result meeting its predetermined specification.

Validation normally required for processing, equipment’s services, production process, test procedure & computer system. The parameters, considered for the validation, are

–          Linearity

–          Accuracy (Recovering)

–          Precision (Reproducibility), etc

Validation types

A)  process validation

Depending on when it is performed in relation to production,

Validation can be prospective, concurrent, and retrospective or revalidation (repeated validation).

1.    Prospective validation– Prospective validation is carried out during the development stage by means of a risk analysis of the production process, Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set.
2.    Concurrent validation – Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. The first three production-scale batches must be monitored as comprehensively as possible.
3.    Retrospective validation – Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated.
4.    Revalidation- Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.).

B)   Instrumentation Validation

• This is a process necessary for any analytical laboratory.
• Data produced by “faulty” instruments may give the appearance of valid data.
• The frequency for calibration, re-validation and testing depends on the instrument and extent of its use in the laboratory.
• Whenever an instrument’s performance is outside the “control limits” reports must be discontinued

Equipment records should include:

• Name of the equipment and manufacturer
• Model or type for identification
• Serial number
• Date equipment was received in the laboratory
• Copy of manufacturers operating instruction (s)

C)  Cleaning validation

Strategy on cleaning validation

      Product contact surface

      After product changeover

      Between batches in campaigns

      Bracketing products for cleaning validation

      Periodic re-evaluation and revalidation

D)  Analytical method validation

Sensitive assay procedure:

1. HPLC, GC, HPTLC
2. TOC
3. pH
4. conductivity
5. UV
6. ELISA

Phases of Validation

Validation is broken down into three phases:

• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)

These three protocols are used to define tests that will demonstrate that the process consistently and repeatedly produces the desired product.

      Installation Qualification (IQ)

–        This is the first step in validation.

–        This protocol insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications.

      Operational Qualification (OQ)

–        This step proceeds after the IQ has been performed.

–        In the OQ, tests are performed on the critical parameters of the system/process. These are usually the independent and/or manipulated variables associated with the system/equipment.

      Performance Qualification (PQ)

–        This is the third and final phase of validation.

–        This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable.

      Design Qualification( DQ )

      – Design of the system

–     (e.g. components, type of air treatment needed, materials of construction)

Check

      Precision, linearity, selectivity

      Limit of Detection (LOD)

      Limit of Quantitation (LOQ)

      Recovery, by spiking

      Consistency of recovery

Importance of validation is vital in pharmaceutical company. It is an quantitative approach is needed to prove quality, functionality, and performance of a pharmaceutical/biotechnological manufacturing process.

CONCLUSION

ARISTOPHARMA LTD. is the name of quality. The slogan of ARISTOPHARMA LTD. is “Quality-the unit we count” All the staff of this company believes and follow the sentences “practice GMP and make GMP practice & quality through GMP”

It is really an example of ideal company in all respects in our country. The qualities of all are very fine products in comparison with other products of market as quality is the measure of excellence. By using the modern developed instrument & technology and all time observing the manufacturing instructions, ARISTOPHARMA LTD. is giving the most quality product to the markets. For this reason both patient and physician easily prefer the products of ARISTOPHARMA LTD. Management system of this company is dynamic and documentation systems excellent.

So, we feel ourselves lucky to complete our in-plant training in this company.

We wish ARISTOPHARMA LTD. would develop day by day and achieve its goal.

Some are parts:

Plant Training on Aristopharma Ltd (Part 1)

Plant Training on Aristopharma Ltd (Part 2)