Month: April 2020

Clinical Trial Requirement and Rules

What is Clinical Trial :

Any systematic study  which is performed on pharmaceutical products in human body whether in patients or other volunteers, in order to  verify the effect or to identify any adverse reaction, or to study absorption, distribution, metabolism and excretion of the products with their efficacy and safety.

It is the only way of establishing the safety and efficacy of any drug before its introduction in the market for human use and is preceded by animal trials where the efficacy and side effects are observed in animals and an estimated drug dose is established.

 Clinical Trials are generally divided into Phases I-IV

Phase I :

These are the First trials of a new active ingredient or new formulation in humans and carried out in healthy volunteers. Their purpose is to make a preliminary evaluation of safety, and an initial Pharmacokinetic/ Pharmacodynamic profile of the active ingredient. Trials can be performed  within a small group of people (typically 20–80) to evaluate safety.

Pharmacokinetics (PK) refers to the movement of drugs through the body, whereas pharmacodynamics (PD) refers to the body’s biological response to drugs.

The purpose is to determine whether the new compound is tolerated by the patient’s body and behaves in the predicted way.

Phase II :

The purpose of these studies is to determine activity and to assess the short-term safety of the active ingredient in patients suffering from a disease or condition for which it is intended.

This phase is also concerned with the determination of appropriate dose ranges and the clarification of dose response relationships in order to provide an optimal background for the design of therapeutic trials.

Trial performed with a larger treatment group (typically 100–300)  to determine efficacy and an optimal dose at which the drug shows therapeutic effect with minimal side effect  combined with further monitoring of safety.

Phase III :

This phase involves trials in large patient group for the purpose of determining the short and long term safety efficacy balance of the active ingredient.

Testing with large groups of people (typically 1,000–3,000) to confirm its efficacy, evaluate its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.

The pattern and the profile of any frequent adverse reactions must be investigated.

The condition under which the trials are conducted   should  be as close as possible to the normal condition of use.

Phase IV :

In this phase studies are performed after the pharmaceutical products  has been marketed and they are based on the product characteristics on which the marketing authorization was granted.

Phase IV trials are conducted as  post marketing efforts to further evaluate the characteristics of the new drug with regard to safety, efficacy, new indications for additional patient populations, and new formulations.

Phase IV clinical trials may include thousands of people and  also called phase 4 clinical trial and post-marketing surveillance trial.

Phase of surveillance after the medicine is made available to doctors, who start prescribing it. The effects are monitored on thousands of patients to help identify any unforeseen side effects.

Clinical Trial Regulatory Requirements in India :

Clinical trials in India are governed by the acts: Drugs and Cosmetics Act, 1940, Medical Council of India Act, 1956 and Central Council for Indian Medicine Act, 1970.

Prerequisites of conducting a clinical trial in India are:

Permission from the Drugs Controller General, India (DCGI)

Approval from respective Ethics Committee where the study is planned

Mandatory registration on the ICMR ( Indian council of Medical Research) maintained website

Clinical Trial New Rules in India :

  • The new rules aim to promote clinical research in India by providing for a predictable, transparent and effective regulation for clinical trials and by ensuring faster accessibility of new drugs to the Indian population.
  • New rules have reduced the time for approving applications, which has now come down to 30 days for drugs manufactured in India and 90 days for those developed outside the country.
  • Drug Controller General of India will decide the compensation in cases of death and permanent disability or other injury to a trial subject.
  • The requirement of a local clinical trial may be waived for approval of a new drug if it is approved and marketed in any of the countries specified by the Drugs Controller General with the approval of the government.
  • Ethics committee will monitor the trials and decide on the amount of compensation in cases of adverse events.
  • It has been mandated that in case of injury to the clinical trial subject, medical management will be provided as long as required as per the opinion of the investigator.
  • New drugs approved for use in select developed markets will be automatically allowed in India provided global trials includes Indian patients.
  • New rules has removed regulations on tests conducted on animals in case of drugs approved and marketed for more than two years in well-regulated overseas drug markets.

Working and Principle of Vibratory Sifter

Vibratory Sifter is used in Sifting of materials in Pharmaceutical manufacturing with different mesh of Sieves and it is widely used equipment in pharmaceuticals and  in food industries.

Uses of Vibratory Sifter :

Sifting is done to remove  lumps or growth that might have formed on the materials after being stored for a longer period and materials are passed through a mesh that opens, which leads to fine the materials. It also removes the unrequired foreign particles and separate the materials according to size 

Types of Vibratory Sifter :

  • One layer, Vibro sifter.
  • Double layer Vibro sifter, which has two layers.
  • Triple-layer Vibro sifter that has three layers.
  • Industrial Vibro sifter which is commonly used in food processing industries.
  • L-shaped sieve frame Vibro sifter.

Different parts of Vibratory Sifter :

Hopper Lid :

Hopper lid is made from metal and this is also called a cover lid.

This component covers the ingredients being processed on the upper section of the machine and it prevents them from falling off whenever the machine is vibrating.

It also helps in preventing the materials from contamination and dusting and it is held up on to the device by a clamping ring.

Filter Screen :

The component aids in providing a smooth surface finish for materials during processing.

The filter screen is made using wire mesh with a fine surface that can sieve the materials properly.

Leakage causes during material processing can be avoided using this component.

It is available in different sizes, and this depends on the machine design.

Wire Mesh Screen Ring :

This is the part where the wire mesh is attached it has a glue that supports the bonding of the mesh to the ring.

This bonding makes the mesh to last longer and helps it remain intact during material processing even with high-intensity vibration.

Oversize Material Outlet :

It can also be called an oversize material chute which discharged the large ingredients after the sieving process is completed.

It is located on the upper part of the device to allow easy and quick discharge of these large particles.

Screen Material Outlet :

This is the opposite of the Over-sized material outlet and it is the outlet for all graded, screened products from the machine.

It is located in the lowest part of the machine which allows easy collection of screened ingredients and quick discharge out of the machine.

Springs :

Springs ensure the machine has a hydraulic movement.

The springs also hold the upper part of the machine as it vibrates and processes the materials.

It’s the springs that allow this device to vibrate freely and prevents the vibration from reaching the floor.

Control Panel :

It has many buttons that are used to send signals to the machine about certain actions it should undertake and control panel displayed all the configured operations.

Motor :

The machine uses electricity, and therefore, it’s this component that converts electricity to the energy that runs the machine.

Multiple plane vibration motion by the motor generates more power, which increases the ingredient particle passing rate through sieves.

The motor size of a Vibro sifting machine may be different because of the machine size, production capacity, and design.

Refer the Calibration of Sieve and Screen

Refer Static charges in Manufacturing

Working and Principle of Rapid Mixer Granulator (RMG)

The Rapid Mixer Granulator was used in pharmaceutical Industry and it is used to mix the pharmaceutical ingredients and make the granules. It is a part of Wet Granulation before Compression & Capsule Filling. It is also called high shear mixer.

Different parts of RMG :

RMG having different parts like Impeller, Chopper, Discharge port, Pneumatic system and control panel etc….

Impeller :

Dome with Impeller and Chopper

At the bottom of the dome shaped stainless steel bowl Impellers are fixed with two half-length blades and two full length blades. Impeller is designed in such a way that full length blades push the material and half-length blade lift the material. Impeller helps to break the wet mass into small pieces and granules.

Chopper :

Chopper has very sharp small blades which are specially designed to cut the wet lumps of material into very small parts which are then mixed by impellers. It is located at bottom of the dome and the size of the granules is totally depends on the speed of the chopper. Chopper blades rotates at a high speed 1500 to 3000 RPM.

Discharge port :

Discharge port is used to unload the container filled with granules. It is located at the bottom of the dome and opening of discharge port is operated by pneumatic cylinder, a compressed air regulated cylinder.

Pneumatic system :

This system is used for operating the discharge valve air purging of chopper drive and the impeller drive to avoid cross contamination. The system also contains air filter pressure gauge and other pipes and pneumatic fittings.

Control Panel :

The Control panel is mounted on the platform and has On/Off, fast, slow, and auto/manual controls. There are a timer, indicator lights, controls for discharge opening / closing, ammeter/voltmeter for motors, air regulator and pressure gauge, air filter, and PLC control panel (optional).

Working principle of RMG :

  • After Loading the ingredients in the RMG the formation of granules occurs by the impeller which sets the entire mixture in a spinning tumbling motion which results in distribution of all dry granules as well as Wet granules.
  • The large lumps formed during wet mixing are broken up by the chopper and during the addition of Binder solution both the Impeller and chopper are operated at slow speed.
  • After formation of Wet mass the speed of Impeller and chopper are operated at High speed to obtain the required size of Granules.
  • Then the wet granules can be discharged with the impeller running through the outlet located on the side of the mixing bowl flush to the bottom.

Over-the-counter (OTC) Drugs and Different Countries Regulation

Over-the-counter (OTCdrugs are the medicines that can sold directly to a consumer without a prescription from a healthcare professional.

The term over-the-counter (OTC) refers to a medication that can be purchased without a medical prescription

Prescription Drugs are the medicines which may be sold only to consumers having a valid prescription.

Prescription drugs require a prescription from a doctor and should only be used by the prescribed individual.

In many countries OTC drugs are selected by a regulatory agency to ensure that they contain ingredients that are safe and effective when used without a physician’s care.

Some drugs may be legally classified as over-the-counter (i.e. no prescription is required), but may only be dispensed by a pharmacist after an assessment of the patient’s needs or requirements.

Regulations detailing the establishments where drugs may be sold, who is authorized to dispense them, and whether a prescription is required vary considerably from country to country.

Different Counties Regulations for OTC Drugs:

Canada :

 In Canada, there are four drug schedules:

Schedule 1: Requires a prescription for sale and are provided to the public by a licensed pharmacist.

Schedule 2: Does not require a prescription but requires an assessment by a pharmacist prior to sale. These drugs are kept in an area of the pharmacy where there is no public access and may also be referred to as “behind-the-counter” drugs.

Schedule 3: Does not require a prescription but must be kept in an area under the supervision of a pharmacist.

Unscheduled: Does not require a prescription and may be sold in any retail outlet.

All medications other than Schedule 1 may be considered an OTC drug, as they do not require prescriptions for sale.

India :

In November 2016, India’s Drug Consultative Committee announced it was begin on establishing a definition of drugs which could be dispensed without a prescription.

Commonly used analgesics like paracetamol and ibuprofen and  medicines for cough, cold and flu fall under the OTC category. 

Netherlands :

A drug that is UA can be sold OTC but only by pharmacists.

A drug that is UAD can also be sold at drugstores, stores where no prescription can be filed and there is only a relatively small selection of popular drugs like painkillers and cough medicine.

The drugs are usually on the shelves, and the store also sells items like toys, gadgets, perfumes and homeopathic products.

Drugs in the AV category can be sold at supermarkets, gas stations etc. and include only drugs with minimal risk to the public, like paracetamol up to 20 tablets, 200 mg ibuprofen up to 10 tablets, cetirizine and loperamide.

United States :

In the United States, the manufacture and sale of OTC substances are regulated by the Food and Drug Administration.

Examples of OTC substances approved in the United States are anti fungal and  analgesics such as lidocaine,  aspirin,  eczema topical treatments, anti-dandruff shampoos and other topical products with a therapeutic effect.

The FDA requires OTC products to be labeled with an approved “Drug Facts” label to educate consumers about their medications. The labels include information on the product’s active ingredient(s), indications and purpose, safety warnings, directions for use, and inactive ingredients.

United Kingdom  :

Prescription Only Medication (POM), which are legally available only with a valid prescription from a prescriber and A pharmacist has to be on the premises for POM medicines to be dispensed, required by law.

General Sales List (GSL), available off the shelf with no pharmacy training required to sell (so they can be sold anywhere, such as supermarkets) and  In general, they are considered safe for most people when taken correctly.

Pharmacy Medicines (P) are medicines which are legally neither a POM or GSL medication and these can be sold from a registered pharmacy and a medical prescriber.

Examples of these include some sleep aid tablets such as  human deworming tablets such as Mebendazole, painkillers and pseudoephedrine.

Working & Principle of Tablet Compression machine

A tablet press is a mechanical device that compresses powder into tablets of uniform size and weight. A tablet press can be used to manufacture tablets of a wide variety of materials, including pharmaceuticals, Nutraceuticals, cleaning products, industrial pellets and cosmetics.

To form a tablet, the granulated powder material must be metered into a cavity formed by two punches and a die, and then the punches must be pressed together with great force to fuse the material together.

There are 2 types of tablet presses: Single station tablet press & Multi-station tablet press.

Different parts with mechanism of Compression Machine are given below :

Tablet Compression machine Hopper

Feeder System

Tablet Compression Punches system

Tablet Compression Dies system

Tablet Compression Turret

Tablet Compression Cam tracks

Tablet Compression Filling station and weight control

Tablet Compression Rollers

Tablet Compression Ejection Cam

Take off Blade and Discharge Chute

Tablet Compression Machine Hopper :


The tablet compression process starts from here and blend or powder has to put in hopper which are compress into tablets.

Depending on the design of a tablet compression machine, we can fill the powder manually or using other automated systems.

Feeder System :

Feeder System

The design of the feeder system should be such that it allows an accurate and consistent amount of powder or Blend to flow to the punch and die system.

Tablet Compression Punches (You can see in the animation Below) :

Punches and Dies

In any tablet press machine, we have

Upper punch system :

The upper punches are on the upper section of the rotary system and they move vertically, in and out of the die bore.

Lower punch system :

The lower punches are on the lower section of the rotary system of the tablet press machine and during the tablet compression process, the lower punches remain within the die bore throughout the entire cycle.

Tablet Compression Die System (You can see in the animation Above) :

The movement of tablet press machine punches, takes place within the die bore or cavity.

It is in the die cavity that the powder is compressed into desired tablets of definite thickness and size and die cavity determines both the thickness and size of a tablet.

Therefore, the punch and die must be machined together to ensure compatibility.

Tablet Compression Turret :

Turret System

The turrets are the heart of tablet press tooling.

The rotating turrets have holes that host the die system and they are precisely machined to ensure both die pockets and punch guided are fully aligned for tablet making

Every bore on its surface ensures the die and punch are fully aligned for optimal tablet making process.

A segmented rotary turret design increases production, while minimizing possible downtime during the manufacturing process and it determines the number of stations.

Tablet Compression Machine Cam Tracks (You can see in the animation Above):

Cam tracks are other critical tablet compression machine parts that play an integral role in ensuring smooth tableting process. The main work of the cam tracks is to guide the upper and lower punches in different stages in the tablet compression process.

As the turret rotates, it is the cam tracks that move the punches in an up and down motion which helps to control filling, compression and ejection of already processed tablets.

For example, as the upper cam withdraws top punches from the die, powder flows in filling the cavity.

On the other hand, the lower cam track pushes the bottom punches upwards within the die cavity. This makes the die to be overfilled by material, allowing for accurate adjustment of the die content.

Again, to achieve a maximum compression force, the upper cam track drives the top punch and the lower cam adjusts the bottom punch.

It is a simple process that must be precisely controlled to achieve the desired tablet size and weight.

Tablet Compression Filling Station & Weight Control (You can see in the animation Above) :

Weight control

By controlling the depth fill, tableting machine can easily regulate the content within its die cavity. Normally, with the help of lower cam track, the bottom punch moves upwards to a predetermined height.

This ensures the die cavity is filled to a required depth before any compression process begins.

At times, as the bottom punch moves up, the excess powder may overflow. Therefore, to avoid wastages, the excess powder automatically moves to the next die cavity, which is just about to be filled.

Compression Rollers (You can see in the animation Above) :

The idea here, is to ensure only powder is compressed to the desired shape and size. However, at times you may find air within the powder particles.

To achieve this, tablet compression machines feature a series of rollers that exert a sufficient amount of force to compress the powder and they expel air first before the compression process begins.

Pre-compression rollers

These are the very first rollers in rotary tablet press. Basically, these rollers apply a small amount of force on the upper and lower punches.

This gives the initial compression force. The aim of this process is to remove air that could be in the die or powder particles.

Main compression rollers

Main compression rollers exert a predetermined amount of force (final compression force) for the formation of tablets. The compression force at this stage is higher than the pre-compression force.

It is important that the rollers remain stable with no vibration during the entire process. This is to ensure consistency of the tablets’ thickness and size.

Tablet Compression Ejection Cam (You can see in the animation Above):

The ejection cam is located just after the main compression rollers and like the other cam tracks, ejection cams are also critical aspects of tablet compression machine parts.

Remember, after compression, the tablet is always fixed within the die systems (space between lower and upper punches).

The ejection cams steadily and slowly push the bottom punch upwards. At the same time, the top cams move up and so are the top punches.

As a result, the fully compressed tablets leave the die cavity, i.e. the compressed tablet remains just at the top of the die.

Take –off blade and Discharge Chute :

The take –off blades are fitted just above the feeder housing. Their main role is to deflect the fully compressed tablets into the discharge chute.

The discharge chute, then directs the tablets to a collection bin.

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5S in Pharmaceutical Industry

What is 5S System:

5S is a system for organizing spaces so that work can be performed efficiently, effectively, and safely. This system focuses on putting everything where it belongs and keeping the workplace clean, which makes it easier for people to do their jobs without wasting time or risking injury.

5S methodology has expanded from manufacturing and is now being applied to a wide variety of industries including Health care or pharmaceuticals, Education and Government. it can also be applied to knowledge economy work, with information, software, or media in the place of physical product.

Origin of 5S System :

5S was developed in Japan and was identified as one of the techniques that enabled Just in Time manufacturing.

5S began as part of the Toyota Production System (TPS), the manufacturing method begun by leaders at the Toyota Motor Company in the early and mid-20th century.

This is often accomplished by finding and eliminating waste from production processes.

5S Translation :

The term 5S comes from five Japanese words:

  • Seiri
  • Seiton
  • Seiso
  • Seiketsu
  • Shitsuke

In English, these words are often translated to:

  • Sort
  • Set in Order
  • Shine
  • Standardize
  • Sustain

What are the Benefits of 5S :

  • Reduced costs of the organization
  • Can produce High Quality of Products
  • Increased the productivity
  • Greater employee satisfaction
  • A safer work environment  for the personnel working in the organization

Sort (seiri) :

Seiri is sorting through all items in a location and removing all unnecessary items from the location.


  • Reduce time loss for searching an item by reducing the number of items.
  • Reduce the chance of confusion by unnecessary items.
  • Simplify inspection.
  • Increase the amount of available, useful space.
  • Increase safety by eliminating obstacles.


  • Check all items in a location and evaluate whether or not their presence at the location is useful or necessary.
  • Remove unnecessary items as soon as possible. Place those that cannot be removed immediately in a ‘red tag area’ so that they are easy to remove later on.
  • Keep the working floor clear of materials except for those that are in use to production.

Set in order (seiton) :

 Seiton is putting all necessary items in the optimal place for fulfilling their function in the workplace.


  • Make the workflow smooth and easy.


  • Arrange work stations in such a way that all tooling / equipment is in close proximity, in an easy to reach spot and in a logical order adapted to the work performed. Place components according to their uses, with the frequently used components being nearest to the workplace.
  • Assign fixed locations for items. Use clear labels, marks or hints so that items are easy to return to the correct location and so that it is easy to spot missing items.

Shine (seiso) :

Seiso is sweeping or cleaning and inspecting the workplace, tools and machinery on a regular basis.


  • Improves the production process efficiency and safety, reduces waste, prevents errors and defects.
  • Keep the workplace safe and easy to work in.
  • Keep the workplace clean and pleasing to work in.


  • Clean the workplace and equipment on a daily basis, or at another appropriate (high frequency) cleaning interval.
  • Inspect the workplace and equipment while cleaning.

Standardize (seiketsu) :

Seiketsu is to standardize the processes used to sort, order and clean the workplace.


  • Establish procedures and schedules to ensure the repetition of the first three ‘S’ practices.


  • Ensure everyone knows their responsibilities of performing the sorting, organizing and cleaning.
  • Use photos and visual controls to help keep everything as it should be.
  • Review the status of 5S implementation regularly using audit checklists.

Sustain/self-discipline (shitsuke) :

Shitsuke or sustain the developed processes by self-discipline of the workers.

Also translates as “do without being told”.


  • Ensure that the 5S approach is followed.


  • Organize training sessions.
  • Perform regular audits to ensure that all defined standards are being implemented and followed.
  • Implement improvements whenever possible. Worker inputs can be very valuable for identifying improvements.
  • When issues arise, identify their cause and implement the changes necessary to avoid recurrence.

Hold Time Study in Pharmaceutical Manufacturing

What is Hold time Study:

Hold Time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not degrade significantly during the hold time at a required temperature and Relative Humidity.

Hold time can be considered as the established time period for which materials (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications.

Hold-time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not produce results outside the acceptance criteria during the hold time.

Hold times should normally be determined prior to marketing of a product and the risk assessment of changes in processes, equipment, storage conditions, starting or packaging materials should include an assessment of whether further hold-time studies should be performed.

Manufacturers may use a flow chart to review the manufacturing procedure for a product and then break up the critical stages of the manufacturing process on the basis of the time period required for the particular storage and processing stages.

The following stages shall be considered for Hold time Study :

Binder preparation to granulation – consider the Binder preparation for Hold time

Wet granulation to drying – consider the dried granulate for Hold time

Lubrication/blending – consider the lubricated blend for Hold time

Blend to compression– consider the compressed tablets for Hold time

Blend to Capsule Filling– consider the Filled Capsule for Hold time

Compression to coating – consider the coated tablets for Hold time

Coating solution to preparation – consider the coating solution for Hold time

Hold time Study Protocol Contains :

A written Hold time study Protocol should be followed which includes the activities to be performed, test parameters and acceptance criteria appropriate to the material or product under test.

The protocol and report should generally include the following: a title; reference number; version; date; objective; scope; responsibility; procedure; description of the material or product; sample quantities; sampling method and criteria; acceptance limits; frequency of sampling; sampling locations; pooling of samples; storage conditions; type of container; methods of analysis; results; conclusion; recommendation; signatures; and dates.

A representative sample of the batch of material or product subjected to the hold-time study should be held for the defined hold period. The hold period for each category of material should be established on the basis of the study by keeping the material in either the original or simulated container used in production.

The containers in which hold-time samples are stored should be the same pack as is used in production may be used and reducing the size of container, when this is necessary for testing holding time, should be justified.

The environmental conditions for sample storage should be the same as those of the manufacture stage and a sampling plan should be established and followed for taking samples for testing at the different intervals.

At different intervals samples shall be send to Quality Control for analysis.

The amount of sample required should be calculated based on the batch size, the intervals, and the tests to be performed.

Sampling Interval for Hold Time Study :

Reference : WHO Annex 4 TRS 992 General Guidance on Hold time Studies

Corrective Action and Preventive Action (CAPA)

CAPA is taken to correct or rectify the problem or incident or deviation or event etc.

Corrective Action :

An action taken to eliminate the cause of the existing deviation , incident or problem in order to prevent its reoccurrence (occurring again).

Preventive Action :

An action taken to eliminate the cause of potential deviation, incident or problem in order to prevent its occurrence (an incident or event).

Corrective Action and  Preventive Action can be routed or generated from the following activities (But not Limited To ) :

  1. Deviation

2. Customer and Regulatory Audits at the site

3. Critical equipment / instrument breakdown

4. Customer/ Regulatory complaints or Market Complaints

5. Product recalls

6. Repeated failures of the systems

7. Vendor audits

8. Self Inspection at site (whether Internal or Corporate Quality Assurance)

9. Rejections of the material (Raw materials, Packing materials and Finished Product)

10. Management review meetings for the GMP system

11. Annual Product Quality Reviews

12. Out of Specification

13. Out of Trend

14. Incidents

15. Mock exercises e.g. recall, safety mock drill, etc

Procedure :

Based on the investigation report the Head of impacted department or the Investigation team shall identify and propose the CAPA to address the incident occurred and avoid its reoccurrence

The responsible department Head/Designee shall fill the CAPA form and send the CAPA form to QA.

CAPA shall be Approved by Head QA/Designee  & after approval from Head Quality Assurance CAPA number shall be allotted and the same shall be entered in CAPA Logbook.

Monitoring, Completion and verification of CAPA :

Authorized persons from QA shall monitor the CAPA for its completion.

On Completion of required actions the department head shall certify that proposed CAPA is completed and implemented.

QA shall verify the implementation and completion of CAPA by review of supporting documents and certify the same.

Based upon the CAPA the required changes done shall be shared to the user and other impacting department and required training shall be imparted.

CAPA shall be completed and closed within the Target Completion date (TCD) and if not completed within the TCD can be revised with appropriate justification.

Two extensions shall be allowed and if the CAPA is not completed after second extension then Quality Risk Assessment report shall be prepared by the user department.

Effectiveness of CAPA :

CAPA effectiveness shall be done with Trend review of various CAPAs derived from incidents or events.

CAPA effectiveness check include the review of the repetitive CAPAs & the same shall be considered satisfactory if no repetitive CAPA is observed.

CAPA effectiveness check can also be verified from the review system like Annual Product Quality Review and during internal audit.

Spot Check can also performed for CAPA effectiveness check. Example Suppose some procedure was newly implemented in batch record & training was imparted for the same but whether the same is followed or not that has to be checked.

Monitoring is used for real-time observations over a defined period to check CAPA effectiveness.

CAPA should be review Annually which contains number of CAPA initiated throughout the year, Open & closed CAPAs, Department wise, number of CAPA closed within Target completion date (TCD) etc.

CAPA Form is given Below for Reference :

Pharmaceutical Plant Contract Manufacturing and Contract Analysis as Per GMP

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises, Equipment’s, Production, Training, personnel Hygiene, Self-Inspection, quality audits and suppliers’ audit, Personnel, Quality Control, and Complaints & Recall. There are various modules of GMP which I will share one after another & today’s module is Contract Manufacture and Contract Analysis.

The Contract Analysis :

What is Contract :

The definition of a contract is an agreement between two or more people to do something. Example suppose X company is manufacturing some products for Y Company so here X Company is called Contract Acceptor and Y Company is called as Contract giver.

Contract should describe clearly who is responsible for purchasing materials, testing & releasing them, undertaking production & quality controls including the in-process control and who has responsibility for samples & analysis.

There must be a written contract between the contract giver and the contract acceptor which clearly establishes the responsibilities of each party, covering the outsourced activities, the products or operations to which they are related, communication processes relating to the outsourced activities and any technical arrangements made in connection with it.

The contract must clearly state the way in which the authorized person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the marketing authorization.

Technical aspects of the contract should be drawn up by competent persons with suitable knowledge of pharmaceutical technology, analysis and GMP.

All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties.

The contract should clearly describe who is responsible for contracted activities, e.g. knowledge management, technology transfer, supply chain, subcontracting, testing and releasing materials and undertaking production and QC, including in-process controls, and who has responsibility for sampling and analysis.

Manufacturing, analytical and distribution records, and reference samples, should be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect, or to investigating in the case of a suspected falsified product or laboratory fraud, must be accessible and specified in the procedures of the contract giver.

The contract should describe the handling of starting materials, intermediate, bulk and finished products, if they are rejected. It should also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected.

General Requirements :

Contract production, analysis and any other activity covered by GMP must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product, or analysis, of unsatisfactory quality.

All arrangements for contract production and analysis, including technology transfer and any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned.

The contract should permit the contract giver to audit the facilities and activities of the contract acceptor or mutually agreed subcontractors.

In the case of contract analysis, the final approval for release must be given by the authorized person in accordance with GMP and the marketing authorization as specified in the contract.

Responsibilities of contract Giver :

Before giving contract to a company or organization the contract giver shall perform audit which includes the premises, Facility, Equipments, System etc and after satisfactory outcome the contract giver has to give the contract to the respective company or the contract acceptor for manufacturing of products.

The Pharmaceutical Quality System of the contract giver should include the control and review of any outsourced activities.

The contract giver is responsible for assessing the legality, suitability and competence of the contract acceptor to successfully carry out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of GMP are followed.

The contract giver should provide the contract acceptor with all the information necessary to carry out the operations correctly in accordance with the marketing authorization and any other legal requirements. The contract giver should ensure that the contract acceptor is fully aware of any hazards associated with the product, work or tests that might pose a risk to premises, equipment, personnel, other materials or other products.

The contract giver should review and assess the records and results related to the outsourced activities. The contract giver should ensure that all products and materials delivered by the contract acceptor have been processed in accordance with GMP and the marketing authorization; comply with their specifications and that the product has been released by the authorized person in accordance with GMP and the marketing authorization.

The contract giver should monitor and review the performance of the contract acceptor including the implementation of any needed improvements and their effectiveness.

The contract giver is responsible for ensuring that the contract acceptor understands that his or her activities may be subject to inspection by competent authorities.

Responsibilities of Contract Acceptor :

The contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the contract giver.

Contract manufacture may be undertaken only by a manufacturer who holds a valid manufacturing authorization.

The contract acceptor should not pass to a third party any of the work entrusted to him or her under the contract without the contract giver’s prior evaluation and approval of the arrangements.

Arrangements made between the contract acceptor and any third party should ensure that information and knowledge, including that from assessments of the suitability of the third party, are made available in the same way as between the original contract giver and contract acceptor

The contract acceptor should refrain from any activity (including unauthorized changes outside the terms of the contract) that may adversely affect the quality of the product manufactured and/or analysed for the contract giver.