Month: March 2019

Process Validation Sample Protocol

Protocol Approval :

Protocol shall be prepared by Quality Assurance or Technology Transfer department and Shall be Reviewed by Production, Quality Control, Regulatory affairs (for regulatory filling) , Qualified person or customer (if required) and Approved by Quality assurance. Before start of the activity protocol shall be approved and Training shall be imparted to the concern personnel .

Reason for Validation :

Reason for validation contains why validation has to performed or taken for __________product.

Objective :

The objective of this protocol is to validate the manufacturing process [i.e Blend, compression and coating] of Product ______________ by studying three consecutive batches produced in accordance with the Batch Processing or Manufacturing Record using qualified equipments and utilities in production, ________ Company with location.

Scope :

The scope of this protocol is limited to validate the manufacturing process Blend, compression and coating of   Product ________ by using qualified equipments in Production Block, for a batch size of _______ Tablets equivalent to ______ Kg.

Reason for Validation :

First commercial Validation batches to US or Europe or other Market

Execution Team or Responsibility :

Identify representatives from different departments and record the same in Process validation Report. Responsibilities of various departments are given below. Production to Manufacturing of product as per batch record, Quality Assurance shall Monitoring, Sampling and reviewing the validation activities, Technology transfer for Process monitoring and Evaluation and Quality control for Testing of sample

Product Information :

Product Information shall contains Product name, generic name, storage condition, category i.e antibiotic or other etc and shelf life. For shelf life note shall be mentioned as Shelf life is tentative and will be re-ascertained based on the real time stability data.

Product description and Manufacturing Formula :

Raw materials to be used in the manufacturing shall be procured from the approved vendors and shall meet all the specifications.

Product description contains label claim, Batch size and Shelf life

Manufacturing formula contains Sr. Number, Item Code, Name of Ingredients, Specification, Label claim, Source of Ingredients, Qty. mg/ Capsule/tablet and Qty./Batch etc.

Process Flow Diagram :

Process Flow Diagram contains the processing steps of the product which include Dispensing of Materials, Sifting, Milling, Dry mixing , wet mixing, Drying, Blending, Compression or Capsule filling, Coating, Inspection etc.

Rational for selection of critical steps, its process parameters for validation and  list of critical process variable :

Speed of blender (RPM) and blending time are the critical variables in blending process as step involves the blending of all the materials together,The speed of compression machine is critical in obtaining tablets of desired physical characteristics and the speed of machine affects the Weight variation and uniformity of dosage units, Coating involves Speed of coating pan, speed of peristaltic pump, Inlet temperature, Exhaust temperature, atomization pressure used during coating process are critical, needs to be controlled to have better uniformity in coating.

Critical Process Variables which includes CPP (Critical process Parameters) and CQA’s (Critical Quality Attributes). CPP includes Blending & Lubrication time and RPM of Blender, Compression and Capsule Filling machine speed etc. CQA’s includes Blend Uniformity (BU), Dissolution, Uniformity of dosage units by mass variation and Related substances.

List of equipment / instruments used :

List of equipment  / instruments used in the Manufacturing process, Operation SOP Number, Qualification status, Calibration status and Preventive maintenance status etc and same shall be recorded in report.

Sampling and Testing plan :

Sampling and Testing plan which contains the Variables like Blender speed and Blending time in Blending stage, Different speed challenges and Hopper Study at Compression and Capsule Filling Stage, pan speed, spray rate, Inlet temperature and exhaust temperature at Coating stage.

Sampling plan which includes Quantity of sample to be collected in each stage

Control/Evaluation parameters which includes Blend uniformity, assay, Loss on Drying, Bulk and tapped density, Sieve analysis etc. at blend stage and Assay, Uniformity of dosage units (by mass variation), Dissolution and complete analysis at compression and capsule Filling stage and coating stage.

Environmental Control :

It includes the temperature and Relative Humidity which is required at Dispensing / Sifting / Blending/compression/capsule filling/coating/inspection stage

Batch Yield at Various Stages :

The details of yield at all stages of the manufacturing shall be recorded in the report i.e at Blend , Compression, capsule filling, Coating and inspection stage etc.

Stability Study Requirement :

Batches of finished drug product of ____________ will be kept on stability as per the stability protocol. It specifies the required numbers of batches to be taken for stability.

Review of deviation, out of trend results, out of specification results and CAPA:

Any observation or change that is required to be made in the Validation batch shall be noted in the history sheet of the Batch record. The change shall be noted in the report.

Change control will be raised for any changes to be done in specifications or in the BAtch record based on the data of the Validation batch, with scientific justification without affecting the registered specifications of the product.

Revalidation Criteria:

The manufacturing process of __________ shall be revalidated as per SOP whenever there is a change in manufacturing formula / manufacturing process/ Ingredient manufacturer / manufacturing equipment / manufacturing site. The implementation of these changes shall be carried out as per change control system.

Summary and conclusions:

Conclusions shall be made on the validity of the manufacturing process in individual runs and on the three consecutive validation runs. It is based on the result obtained after execution of the batches which includes the critical parameters and shall be recorded in the Validation report.

Reference Documents :

Reference Documents shall include Master Formula record, Batch Manufacturing record, Specification (Blend, Intermediate & Finished etc.) which are required in the batch or product. Always referred current version of all documents.

Abbreviation (s)

Mention the Abbreviation of the words used in the protocol for easy understanding and for better clarity.

Related topic https://pharmaceuticalupdates.com/2019/03/11/process-validation-in-pharmaceuticals-manufacturing/

Process Validation in Pharmaceuticals Manufacturing

What is Process Validation:

Process validation is defined as the collection and evaluation of data from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. Process validation activities categorized in three stages, such as

Stage 1 as Process Design:

The process is defined during this stage based on knowledge gained through development and scale-up activities such as lab scale / trial batches and optimization / pre – validation batches.

Stage 2 as Process Qualification:

During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing with three consecutive validation batches.

Stage 3 as Continued Process Verification:

Ongoing assurance is gained during routine production that the process remains in a state of control through product Quality review.

General Instructions :

  • Any changes during the project phase or during commercial production, the risk assessment shall be performed, as required.
  • Quality Risk Assessment (QRM) shall be performed prior to execution of new product.
  • Process knowledge from development studies should be available to the manufacturing site, unless otherwise justify, and be the basis for validation activities.
  • Batches under Process validation shall be released for distribution after following
  1. Drug Product should be fully complying with cGMP, with the validation acceptance criteria.
  2. Any deviation observed during validation has been assessed to have no impact on product quality prior to release of batches.
  3. Finished product samples of batches are tested as per ‘Release’ specifications and found to be satisfactory
  4. The batches meet all other requirements as per Batch release procedure.
  5. Raise deviation and perform investigation if any significant changes to the approved protocol during execution.

Process Design:

  • The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
  • A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control that is appropriate for the manufacturing process.
  • Formulation Research and Development shall develop the product based on their development studies. Formulation Research and Development shall provide key inputs to process design and quality attributes for manufacturing process.
  • Formulation Research and Development or shall document this information and same information shall be considered for process qualification and continued process verification stage of process validation.
  • Formulation Research and Development shall define process control for each process operation and overall process based on process knowledge & understanding gained during product development.
  • Trial batches, Pre-validation/ Optimization batches shall be a part of Process design phase.

Process Qualification:

  • During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
  • Validation team shall ensure that equipments and utilities are qualified before manufacturing of commercial batches for process performance qualification.
  • Process Performance Qualification has to perform to confirm that the process design is capable of commercial manufacturing as expected.
  • This stage needs to be completed prior to commercial distribution.
  • Following activities shall be completed before Process Performance Qualification as follows
  1. Manufacturing facility has been qualified to meet cGMP requirements.
  2. Equipment to be used in manufacturing has been qualified.
  3. Utilities to be used in manufacture of the product (example- Purified Water,Compressed Air, HVAC Systems etc.) have been qualified.
  4. Instruments used in processing have been calibrated (example- Temperature Sensors, Weighing Balance etc.)
  5. Trained Personnel shall be involved in manufacturing, testing and in process control.
  6. Process Performance Qualification &  Exhibit Batch Protocol shall be prepared and approved
  7. All the activities shall be performed as per Approved validation Protocol.
  8. A product / process shall be considered as qualified when qualification batches meet the acceptance criteria established in the protocol.
  9. In case a batch fails to meet acceptance criteria established for the particular product, complete investigation shall be carried out to find cause of failure.
  10. Decision regarding repeat the batch manufacturing for qualification batch, to implement a process change or repeat the sample analysis shall be taken .
  11. The decision will be based on findings of investigation and If required necessary inputs shall also be taken R & D (F) need based.

Continued Process Verification:

  • Objective of this stage of process validation is continual assurance that the process remains in state of control and in validated state during commercial manufacturing.
  • During this stage monitoring of critical process parameters and critical quality attributes at the level established during the process qualification stage shall be done.
  • In case of new drug products, Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) to be monitored as a part of continued process verification shall be as per (but not limited)  Process performance qualification protocol.
  • In case of existing drug products, Production and Technology Transfer department shall identify the Critical Process Parameters (CPPs) & Critical Quality Attributes (CQAs) to be monitored. Identified Critical Process Parameters (CPPs) & Critical Quality Attributes (CQAs)
  • Quality Assurance shall ensure that CPPs and CQAs value are within control limits prior to release of batch. This shall be enclosed with Batch Manufacturing Record.

Critical Process Parameters (CPP):
These are key variables affecting the production process. CPPs are attributes that are monitored to detect deviations in production operations and product output quality or changes in Critical Quality Attributes. These includes the Physical parameters like Impeller and chopper reading, Mixing time, Blender RPM, Compression and coating etc.

Critical Quality Attributes (CQA): A Physical, Chemical, Biological or Microbiological property or characteristic that should be within an appropriate limit and range to ensure the desired product quality. These includes the Analytical Parameters like Assay, Dissolution, Related Substances etc.

Re-validation of Process:

Re-validation to be carried out to evaluate a change in existing process/ equipment/ input materials etc. which will impact product quality.

Re validation may be restricted to a particular process step(s) that is/ are impacted by the change. (Ex: Change of compression machine, change in coating lot size).

Re validation shall be carried out under following criteria ( but not limited to)

  • Change in Batch size (Scale up or Scale down)
  • Change in Manufacturing process
  • Change in Source of API
  • Change in Capacity of Equipment

For more details Refer Below link of FDA Process Validation General Principle and Practices and Eudralex Annex 15 Process validation

Yellow Card in Medicines and Healthcare Products Regulatory Agency (MHRA) and its Reporting details at a Glance

What is Yellow Card Scheme in UK :

The Yellow Card Scheme is the UK system for collecting information on suspected adverse drug reactions (ADRs) to medicines. The Yellow Card Scheme is essential in helping the MHRA to monitor the safety of all healthcare products in the UK to ensure they are acceptably safe for patients and those who use them.

The scheme includes all medicines including vaccines, blood factors and immunoglobulins, herbal medicines, homeopathic remedies, and all medical devices available on the UK market.

The Scheme collects information on suspected problems or incidents involving as follows

  1. Side effects (also known as adverse drug reactions or ADRs)
  2. Medical device adverse incidents
  3. Defective medicines (those that are not of an acceptable quality)
  4. Counterfeit or fake medicines or medical devices
  5. Safety concerns for e-cigarettes or their refill containers (e-liquids)

It is important for people to report problems experienced with medicines or medical devices then MHRA will review the product if necessary, and take action to minimize risk and maximize benefit to the patients.

The MHRA is also able to investigate counterfeit or fake medicines or devices and if necessary to take action to protect public health.

Background of Yellow card Scheme :

The Scheme was founded in 1964 after the thalidomide disaster, and was developed by Bill Inman.

It is run by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Commission on Human Medicines.

It was extended to hospital pharmacists in 1997, and to community pharmacists in 1999.

Suspected adverse reactions are collected on all licensed medicines and vaccines, from those issued on prescription to medicines bought over the counter from a pharmacist or supermarket.

What is Adverse Drug Reaction :

An unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use, which is suspected to be related to the drug or medicine

Serious adverse event or reaction as one when the patient outcome is one of the following.

  • Death
  • Life-threatening
  • Hospitalization (initial or prolonged)
  • Disability – significant, persistent, or permanent change, impairment, damage or disruption in the patient’s body function/structure, physical activities or quality of life.

How are Yellow Card reports used?

The UK medicines regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), runs the Yellow Card Scheme.

It collects reports of side effects from people taking medicines, as well as from healthcare professionals such as doctors, pharmacists and nurses also reporting suspected side effects experienced by a patient.

These reports are used to identify side effects and other safety information about medicines which might not have been known about before.

If a new side effect is found, the MHRA will review the way that the medicine can be used, and the warnings that are given to people taking it.

How to report a suspected side effect :

There are four main ways you can report :

  • complete the attached form, and send it back in the envelope provided (there’s no need for a stamp).
  • call the Yellow Card reporting line on freephone 0800 731 6789 (10am to 2pm Monday-Friday only)
  • using the free app – search ‘Yellow Card’.

What the Yellow card Form Contains : The form has five sections

  1. About the suspected side effect. Give as much information as you can. You can also tell us if the harm was because of a mistake in how you took the medicine or how it was given to you – this is called a medication error. For example: wrong drug, dose or route; and why (such as, too much medicine taken because of wrong instructions on the pharmacy label, or I accidentally took too much, or I was given the wrong medicine etc). All reports are kept in confidence.

2. About the person who had the suspected side effect. Give as much information as you can, such as age, sex, height and weight. This helps us differentiate between patients on our database. It also helps us understand if certain patients are more vulnerable to experiencing a side effect.

3. About the medicine(s) which might have caused the side effect. If you have it, provide the batch number which can be found on the medicines box. Sometimes side effects can also happen because of interactions, so we ask you to tell us about all medicines or herbal remedies being taken.

4. About your doctor (optional). If you give permission for us to contact your doctor, supply contact details.

5. About you – the person making the report. We need a name and contact details, it also helps us get in touch with you if we need more information.

Please sign and date the form before you post it in the attached envelope and if somebody need more space, write it on a separate sheet of paper and enclose it in the envelope with your form.

The MHRA will send an acknowledgement when Yellow Card report is received and if the patience have given permission on the form, MHRA will send a copy to patients doctor.

Medicines and Healthcare products Regulatory Agency (MHRA) and its Role and Responsibility

Who is MHRA :

The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom (UK) which is responsible for ensuring that medicines and medical devices work and are acceptably safe.

When MHRA Formed :

MHRA was formed in 2003 with the merger of the Medicines Control Agency (MCA) and the Medical Devices Agency (MDA). In April 2013, it merged with the National Institute for Biological Standards and Control (NIBSC) and was re-branded, with MHRA identity being used solely for the regulatory center within the group. The Agency employs more than 1,300 people.

MHRA is funded by the Department of Health and Social Care for the regulation of medical devices, while the costs of medicines regulation is met through fees from the pharmaceutical industry.

The MHRA works closely with the European regulator, the European Medicines Agency (EMEA), and is recognised as a trusted and independent source of expertise throughout Europe.

The MHRA also collaborates with other international regulators, such as the US Food and Drug Administration (FDA), and UK government agencies involved in healthcare, including the National Patient Safety Agency (NPSA) and the National Institute for Health and Clinical Excellence (NICE).

Responsibility of MHRA :

  • Operate post-marketing surveillance for reporting, investigating and monitoring of adverse drug reactions to medicines and incidents with medical devices.
  • Assessment and authorization of medicinal products for sale and supply in UK.
  • Supervise the Notified Bodies that ensure medical device manufacturers comply with regulatory requirements before putting devices on the market.
  • Operate a quality surveillance system to sample and test medicines to address quality defects and to monitor the safety and quality of unlicensed products.
  • Investigate sales and potential counterfeiting or fake of medicines, and prosecute where necessary.
  • Regulate clinical trials of medicines and medical devices.
  • Monitor and ensure compliance with statutory obligations relating to medicines and medical devices.
  • Promote safe use of medicines and devices.
  • Manage the Clinical Practice Research Datalink and the British Pharmacopoeia.
  • Perform inspection or audit in manufacturing and processing site for MHRA regulated product that are sold in UK
  • To perform pre-approval inspection after company submits an application to MHRA to market a new product.
  • To review the Product dossier submitted by the company and to provide the product approval

What MHRA do when quality or safety concerns arise :

  • When a product is suspected or known to be faulty, the MHRA immediately works with manufacturers and wholesalers on the most appropriate and timely action to take.
  • Sometimes this means a product has to be recalled and taken out of the supply chain.
  • By law, manufacturers must report to the MHRA any important defects in both medicines and medical devices.
  • The MHRA is committed to responding promptly and appropriately to concerns that cause threat to the public’s health.
  •  Reports prompt investigations, which can result in the issue of warnings and alerts and MHRA also has the power to prosecute when regulations have been defence.
  • The courts can impose fines or prison sentences when the law has been broken and the Agency can withdraw unlicensed/ illegal products from the market.
  • Warnings (Alerts) can be issued about defective medicines, problems with devices, and side effects associated with medicines and blood and blood products.

United State Food and Drug Administration (USFDA) and Form 483 and Warning Letters at a Glance

Who is USFDA :

The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health and Human Services. The FDA was empowered by the United States Congress to enforce the Federal Food, Drug, and Cosmetic Act, which serves as the primary focus for the Agency.

The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate. The Commissioner reports to the Secretary of Health and Human Services. The FDA has its headquarters in unincorporated White Oak, Maryland.

FDA’s organization consists of the Office of the Commissioner and four directorates overseeing the core functions of the agency.

Responsibility of FDA :

  • Protecting the public health by assuring that foods are safe, wholesome, sanitary and properly labeled; ensuring that human and veterinary drugs, and vaccines and other biological products and medical devices intended for human use are safe and effective.
  • Protecting the public from electronic product radiation
  • Assuring cosmetics and dietary supplements are safe and properly labeled
  • Regulating tobacco products Advancing the public health by helping to speed product innovations
  • FDA’s responsibilities extend to the 50 United States, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions.
  • To provide Approval of new drugs & to Perform routine inspection of a regulated facility
  • Inspect the foreign manufacturing and processing sites for FDA-regulated products that are sold in the United States
  • To perform pre-approval inspection after a company submits an application to FDA to market a new product.
  • “for-cause” inspection to investigate a specific problem that has come to FDA’s attention

What is Form 483 :

The U.S. Food and Drug Administration (FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act. Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections. It is also referred to as “Form 483” or merely “483”.

A recipient of a 483 should respond to the FDA, addressing each item, indicating agreement and either providing a timeline for correction or requesting clarification of what the FDA requires.

This response must be submitted within 15 business days.

When is an FDA Form 483 issued :

An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgment, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or may injurious to health.

What is the purpose of an FDA Form 483 :

The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan.

How is the FDA Form 483 shared with the company :

FDA Form 483s are discussed with a company’s management at the conclusion of the inspection. Each observation is read and discussed so that there is a full understanding of what the observations are and what they mean.

What are the implications of the Form 483 for agency enforcement :

The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, (EIR) all evidence or documentation collected on-site, and any responses made by the company. The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health.
The FDA calls for a response to the Form 483 observations within 15 working days.

What is FDA Warning Letter :

An FDA warning letter is an official message from the United States Food and Drug Administration (FDA) to a manufacturer or other organization that has violated some rule in a federally regulated activity which is identified by Inspectors or agency during  inspections or investigations .

A Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act .

When FDA Issues Warning Letter :

  • The FDA calls for a response to the Form 483 observations within 15 working days. Though a written response is not mandatory, it is preferred so that a warning letter can be avoided.
  • The company has to respond to the observations in detail with reasons for the shortcomings and corrective action plans and each observation should be addressed individually.
  • If the management does not convincingly address the Form 483 observations within the specified time period, the FDA issues a warning letter.
  • Sometimes, if the observations are of a severe nature, the FDA may issue a warning letter even without issuing Form 483.
  • The firm’s compliance history, e.g., a history of serious violations, or failure to prevent the recurrence or repeat of violations .
  • The nature of the violation, e.g., a violation that the firm was aware of (was evident or discovered) but failed to correct.
  • The risk associated with the product and the impact of the violations on such risk.

Conclusion :

Unsatisfactory response to the warning letter could lead to further action including import alert for products or the facility, withholding of product approval, and suspension or cancellation of manufacturing license.


Many pharma stocks have taken a beating in the recent past due to adverse Form 483 observations and their escalations into warning letters and import alerts.