Pharmaceutical Updates was started to share knowledge among the pharma professionals & it will become helpful to the pharma Professionals. The author of pharmaceutical updates is Chandrasekhar panda who is having more than 13 years of Experience in Pharmaceutical Quality Assurance department and he has worked in Pharma Companies like Cipla, USV & Aurobindo Pharma Limited.
The Central Drugs Standard Control Organization (CDSCO) is the national regulatory body for Indian pharmaceuticals and medical devices, and serves parallel function to the European Medicines agency of the European Union, the Japan, the Foods & Drugs Administration of the United states and the Medicines and Health care products Regulatory agency of the united Kingdom.
The Central Drugs Standard Control Organization (CDSCO) is the Central Drug Authority for Discharging functions assigned to the Central Government under the Drugs and Cosmetics Act. CDSCO has a good track record with the World Health Organization (WHO) . CDSCO Reports to Drug Controller General of India (DCGI)
Major Role of CDSCO:
Under the Drug and Cosmetics Act, the regulation of manufacture, sale and distribution of Drugs is primarily the concern of the State authorities while the CDSCO Authorities are responsible for approval of New Drugs
To Conduct of Clinical Trials of the drugs.
To check the standards for Drugs.
To control over the quality of imported Drugs in the country and coordination of the activities of State Drug Control Organizations by providing expert advice with a view of bring about the uniformity in the enforcement of the Drugs and Cosmetics Act.
CDSCO along with state regulators, is jointly responsible for grant of licenses of certain specialized categories of critical Drugs such as blood and blood products, I. V. Fluids, Vaccine and Sera.
To conduct Audit for World Health Organization (WHO) along with State Drug Control Organizations & to provide WHO Licence .
CDSCO is constantly working to bring out transparency, accountability and uniformity in its services in order to ensure safety, efficacy and quality of the medical product manufactured, imported and distributed in the country.
Import Registration of drugs and medical devices and provide no objection certificates for export .
Banning of drugs and cosmetics.
Vision of CDSCO :
To Protect and Promote public health in India.
Mission of CDSCO :
To safeguard and enhance the public
health by assuring the safety, efficacy and quality of drugs, cosmetics and
CDSCO has six zonal offices, seven sub-zonal offices, 13 port offices and seven laboratories under its control.
Self Inspection or Internal Audit is a Quality System to check whether activities followed by all departments are according to the written approved procedures and complying with the cGMP and Regulatory Requirements.
What are the Objective of Self Inspection :
Promote awareness for Quality and CGMP within plant
Proactive approach to identify and correct the non conformance
Assure the effectiveness and support continuous improvement of compliance to CGMP and Quality management system.
Develop confidence to minimize and possibly to eliminate the scope for major or critical regulatory findings.
To identify the non-compliance or Gap with respect to Manufacturing Practices of production, Quality Control systems, quality assurance procedures, engineering practices, environmental conditions etc.
Procedure of Self Inspection:
Internal audit shall be carried out by an
organization of its own system, procedures and facilities
It should be conducted in an independent and
details way by competent persons.
Self inspection shall be performed routinely or
when an inspection by the health authorities is announced.
How to Perform Self Inspection :
1.Internal Audit Team shall audit the various departments as per Internal Audit (Self-Inspection) Schedule.
2. The team shall carefully review the documents and records as per the Check List .
3. In the Internal Audit (Self-Inspection) following points and their records needs to be checked (but not limited to)
Material Management : Material handling, Man and Material flow and Record keeping
Production, Packing and In-process Controls
Process Equipment / Instruments
Packaging, Identification Labelling and In-process Controls
Storage and Distribution
Change Control , CAPA (Corrective and Preventive Action)
Validation (Process, Cleaning etc)
Rejection and Re-use of Materials (Raw, Packing material & Finished product etc.)
Complaint and Recalls
Calibration, Validation and Preventative Maintenance of Equipment’s / Instruments.
Documentation and Control
Data integrity of the recorded data in routine documentation.
Training / Records
Laboratory Controls : QC Records / Stability Data of Products / Logbooks
Implementation of Corrective and Preventive Actions
Contract Manufacturing Records (Including Laboratories)
4. On completion of Self-Inspection the audit observations shall be discussed with the respective department head. Audit Team shall prepare the Self-Inspection Compliance Report and forward to Quality Assurance department.
5. The observations during the Self-Inspection shall be taken-up on priority by concerned department in consultation with Quality Assurance & also the Concerned department shall take necessary Corrective and Preventive Action (CAPA) if required to avoid re-occurrence .
Self Inspection as per different regulatory Guidelines :
1.WHO describes about the Good practices in self-inspection in Annexure-3 of sec 8.1 to 8.9
2. Schedule M part I describes about the self-inspection and quality audit in section 15.1 to 15.3 of Good Manufacturing Practices
3. USFDA describes about the Self Inspection in PART 211—e-CFR current data as of January 12, 2016 Title 21 → Chapter I → Sub chapter C → Part 211 → Subpart B → Self Inspection
4. MHRA describes about the Self-Inspection in Section II – 2EU Guidance on Good Manufacturing Practice (GMP) – Self-Inspection.
5. TGA describes about the Self Inspection in Chapter 9 -Quality Management.
1.Self Inspection is a tool for internal improvement with respect to cGMP and Regulatory Requirement.
2. Self inspections should be planned with technical persons, having knowledge with respect to the regulatory requirements in that particular field.
3. The inspection shall be conducted for all the departments in the manufacturing facility as per regulatory requirements at least once in year, based on the organization requirements it can be carried out once in quarterly or Half yearly to make sure that all the systems and procedures are under control.
4. The role of Senior Management of the Firm/Organization is important to compile the observation resulted in the self inspection.
Track and Trace is the operation in which the past and current status information of each drug product is recorded. All the drugs in the market are tracked on the basis of packages using keys of GS1 (Global Standards One) standards. The ability to track each drug unit is provided by gathering the information of each unit in every single step and action and traceability is provided, thus the products can be traced at every phase from its manufacturing until their consumption. This system not only applicable to pharmaceuticals but also for Food, Beverages etc.
What is GS1 (Global Standards One) standards :
GS1 is a not-for-profit organisation that develops and maintains global standards for business communication. The well known of these standards is the barcode, a symbol printed on products that can be scanned electronically.
As per the global standards one (GS1) the manufacturer or exporter of drug formulations would have to print the barcode at different packaging levels – primary, secondary and tertiary – to facilitate tracking and tracing of their products.
Barcode helps in tracking and tracing origin of drugs, which minimises the chances of genuine medicines being considered spurious, sub-standard or counterfeit.
Track & Trace System is applicable to US & Falsified Medicines Directive (FMD) is applicable to European Union (EU)
This system is proposed by the countries including Argentina, Brazil, china, EU, France, India, South korea, Turkey and USA to maintain supply chain integrity & ensure patient safety.This guide also provides information on mandate to be adhered by various stakeholders to ensure regulatory compliance.
US Federal Drug Quality and Security Act – H.R 3204 was introduced on September 27, 2013 . This bill was passed in the House on September 28, 2013 -also refereed as pharma track & trace bill is approved by US Senate as a US Federal law effective on Nov 27,2013. Below is the detailed mandate requirements of the same system.
Manufacturers, wholesalers and repackages required to provide and/or receive pedigree for each transaction.
Manufacturers required to include a product identifier number on each package and homogeneous case of prescription drug products.
wholesalers required to accept or distribute only prescription drug products that include a product identifier.
Dispensers required to accept or distribute only prescription drug products that include a product identifier.
Mandates the full implementation of an inter operable electronic system.
After that Title 1-Compounding Quality Act & Title-2 Drug Supply Chain Security Act (DSCSA)came in US to protect Americans against counterfeit drugs.
Drug Supply Chain Security Act (DSCSA) Purpose & Requirements :
Create a new framework for securing prescription drugs supply chain. The bill also establish a 10 year transition to a unit level tracking system for enhance security.
The following data is required be collected for the DSCSA i.e The National Drug Code (NDC interchangeable with GTIN, FDA) ,The lot number, where the product originated, The expiry date & Serial number (S/N), randomization is NOT required.
United States’ Track and Trace Regulations Overview In 2013, the Drug Supply Chain Security Act (DSCSA) was introduced, which requires all manufacturers to affix 2D barcodes on vaccine units of sale in the next couple of years.
The Drug supply chain Security Act (DSCSA) mandates that manufactures begin serializing all drug products at the saleable unit and case level for the US market starting in Nov.2017, with repackager deadlines beginning in 2018.
It is also called Track and Trace Act. DSCSA adds new sections in the Federal F & DC Act which include requirements for product tracing, identification and verification and standards for license of Third Party Logistic providers (3PLs).
The full complement of US requirements phases in between 2015 and 2023, with challenges for all supply chain companies at different points along the way.
The purpose of the DSCSA is to establish a nationwide drug track and trace system that would potentially eliminate counterfeit or illegitimate or fake medications to enter the market.
Track & Trace System Implementation Status in India :
In India Directive General of Foreign Trade (DGFT) made unique numbers and barcodes mandatory on Primary, Secondary & Tertiary packaging for all Pharmaceuticals exports from the country.
The law also requires incorporation of 2D barcodes (GS1 Datamatrix) on medicines at the strip/bottle/vials level as well as encoding GTIN and unique serial numbers by july 1 2014.
But due to the opposition from the industry the same was not fully implemented in India. The government of India has again extended the date for implementation of track and trace system for exports of drug formulations till July 1 2019 & date was extended earlier also from time to time & last extension was till November 15 2018 .
Track & Trace System Compliance Mandate in India :
Exporter of pharmaceutical products will adopt a track & trace system & incorporate its features for exported medicines using barcode technology as per GS1 global standards as details below….
Primary level Packaging requirement : Incorporation of 2D (GS1 data matrix) barcodes on medicines at Stripe/ vial/bottle etc encoding unique product identification code & unique serial number of the Primary pack.
2. Secondary level Packaging requirement : Incorporation of barcodes (1D or 2D) encoding unique product identification code , Batch number, Expiry date and unique serial number of the secondary pack.
3. Tertiary level Packaging requirement : Incorporation of barcodes (1D ) encoding unique product identification code, Batch number, Expiry date and unique serial number of the tertiary pack (shipper/carton).
Under the track & trace system manufacturers would be required to maintained serialized record of exported pharmaceutical product for a minimum period of 6 months after the expiry date of the product.
Counterfeiting is a growing threat to the patients and pharmaceutical industries globally. Therefore it is important for the pharmaceutical industries to use track and trace systems that are very advanced and designed in ensuring best quality print with high efficiency.
This allows the traceability of the products throughout the process and helps identifying the counterfeit or fake products by use of the stored database, serial number, expiry date and companies logo.
Quality Assurance is a deep concept covering all matters that individually or collectively influence the quality of a product. It is the complete & whole of the arrangements made with the object of ensuring that manufactured products are of the quality required for their intended use.
As per Oxford Reference Dictionary the term quality defines as –“A standard of how good something is as measured against other similar things.”
During the 1980s, the concept of company quality with the focus on management and people came to the fore in the U.S. It was considered that, if all departments follow & approached quality with an open mind, success was possible if management led the quality improvement process.
QA is not only limited to Pharmaceutical manufacturing, but also can be applied to any business or non-business activity, which includes design, consulting, banking,food Industry, beverage industry,cosmetic Industry, insurance, computer software development, retailing, investment, transportation, education, and translation etc.
Quality Assurance is A supporting department to other departments & a decision maker throughout the firm/Organization.
Quality Assurance basically divided into three parts i.e In process Quality assurance or Manufacturing assurance or Shop floor Quality assurance, Documentation Quality assurance & Analytical assurance.
In process Quality assurance or Manufacturing assurance or Shop floor Quality assurance is responsible to ensure the quality of the drug products from Raw material store or warehouse to Release or Dispatch.
Documentation Quality assurance is related to the document related activities which includes Training, Quality Management System, Document Issuance, Market Compliant, Audit Compliance etc.
Analytical Quality assurance is responsible to review the analytical documents which are generated after analysis of drug Products.
Pl find the below detail responsibilities of Quality Assurance or Quality Unit (Starting from Trainee to Head QA) throughout the Plant/Organization (But Not Limited to) .
Note : Some Responsibility of Quality Assurance may vary from organization to organization.
To ensure implementation of cGMP practices on the shop floor during manufacturing activities.
To follow Good Documentation practices and safety instructions.
To provide Line clearance on the shop floor (Manufacturing, Packaging and Warehouse).
In process checks during manufacturing & packing activities.
Sampling of raw materials, packing materials, intermediates, and finished products.
Spot check to verify that operations and systems comply with relevant requirements.
Review of the executed documents and review the documents for compliance including log books, Batch Manufacturing & Packing records, Validation protocols and reports, etc.
To investigate the cause of any non conformance and its corrective / preventive action.
Calibration of In process Quality Assurance (IPQA) instruments.
To ensure the preparation, Issuance, Revision and Retrieval of the documents like Formats, Log books, Batch records & Protocols etc
To ensure proper document control on issued document and master documents.
Control Samples Management.
To prepare the Annual Product Quality Review (APQR) and ensure its implementation.
Preparation of protocols and performing Swab sampling for cleaning validations.
To Prepare & review protocols and support execution of process, cleaning validation.
To perform sampling for hold time studies.
Monitoring of the qualification, calibration and Preventive maintenance schedule for equipment’s and instruments at shop floor.
Preparation and review of departmental SOP’s for cGMP compliance.
Preparation of of Master Formula Record , Batch Manufacturing Record , Mater Packing Record & Batch packing Records
To approve or reject starting materials, packaging materials, and intermediate, bulk and finished products in relation to their specifications.
Compilation and review of the Batch records, Certificate of Analysis, Analytical protocol, etc which are required for release of batches.
Review & approve SOPs, change controls, deviations, Annual Product Quality Reviews, Validation Master Plan (VMP) & Site Master File (SMF).
To review the investigation reports for Incident reports, Out of calibrations, Out of specifications, Out of trends etc.
Review of regulatory requirements and its compliance.
Periodic review of all quality functions and procedure for appropriateness and review of related documents.
Responsible for all SAP, LIMS, ERP etc. transactions related to release, reject or block or unblock of raw material, packaging material, in process product and finished product.
To Provide Final Decision.
To check Tracking, implementation & effectiveness of corrective & preventive action (CAPA) .
To review & Approve the investigation reports, Market Compliant, Out of specifications & Out of trends etc.
Quality Assurance is not only responsible to provide Quality products or to ensure Quality throughout the Firm/Organization but also it is the responsibility of individual personnel as well as the Senior Management.
In recent years, CGMP violations related to data integrity was increased during FDA inspections. In order to protect the public health it is the responsibility of manufacturer/firms to ensure the safety, efficacy, and quality of drug products. As a result of data integrity-related CGMP violations many manufacturer/firms has got regulatory actions, including warning letters, import alerts etc.
However Data Integrity related requirement of FDA is available in 21 CFR Part 211 & 212
In December 2018 FDA has published New data Integrity Guideline which contains guidance on different data integrity issues & let’s have a look on below points.
1.Some questions & answers related to Data Integrity definition like What is Data integrity, What is Metadata, What is Audit Trail, What is Static & dynamic records, what is the term backup, and what are computer or related system.
Metadata : The data that describes the attributes of other data and provides context and meaning.
Audit Trail : A secure, computer generated, time stamped electronic record that allows for reconstruction of the course of events relating to the creation, or deletion of an electronic records. An audit trail is the arrangement of events of the who, what, when & why of a record
Static is used to indicate a fixed-data record such as a paper record or an electronic image and Dynamic means that the record format allows interaction between the user and the record content.
2. Before release of the product to the market the same must be evaluated and maintained by the quality unit. Invalidated test results should be recorded with supporting data. Invalid test results must be documented & justified on the basis of a scientifically investigation. The data in the Paper-based and electronic form should be reviewed & kept.
3.The computer system should be validated . Use of invalidated system may impact on the product quality of the product. so controls should be designed to validate a system for its intended use like software, hardware, and documentation.
4. Computer system must be used & records can be made only by authorized personnel who are competent for that activity. The system administrator role, including any rights to alter files and settings, should be assigned to personnel independent from those responsible for the record content. Computer system access privileges should be given based upon the persons experience & skill. A list of Authorized persons should be displayed in the work place.
5. When login credentials are shared, a unique individual cannot be identified & FDA does not allow to share login information between the persons/users. Person can share read only user account to view data in computer system by which user cannot modify or create or delete data.
6. The CGMP documents or record generated in the form of Binding Logbooks & loose formats must be controlled & all these records should have issuance records. Reconciliation should be made for each issued documents or records.
7. Audit trail review is similar to assessing cross-outs on paper when reviewing data. Personnel responsible for record review under CGMP should review the audit trails that capture changes to data associated with the record as they review the rest of the record. The person supervising or checking the information can also review the Audit Trial data.
8. Audit trail should be reviewed after each significant steps like manufacturing, processing, packing, or holding, and required data should be review before batch release. The review frequency can be decided based upon the evaluation of data criticality, control mechanisms, and impact on product quality.
9.Electronic copies can be used as true copies of paper or electronic records, provided the copies preserve the content and meaning of the original record, which includes all metadata required to reconstruct the CGMP activity and the static or dynamic nature of the original records. True copies of dynamic electronic records may be made and maintained in the format of the original records.
10. PH meters, Conductivity meter and balances may create a paper printout as the original record & in this case, the paper printout or a true copy must be retained The original laboratory records, including paper and electronic records, are subject to second-person review to make certain that all test results and associated information are appropriately reported.
11. Electronic signatures with the appropriate controls can be used instead of handwritten signatures or initials in any CGMP required record. Firms using electronic signatures should document the controls used to ensure that they are able to identify the specific person who signed the records electronically.
12. FDA expects processes to be designed so that data required to be created and maintained & cannot be modified without a record of the modification. For Example HPLC analysis data should be saved upon completion of each step or injection instead of at the end of an injection set, and changes to the data or injection sequence should be documented in an audit trail.
13.System suitability tests should be performed according to the firm’s established written procedures which should include the identity of the preparation to be injected and the rationale for its selection. If an actual sample is to be used for system suitability testing, it should be a properly characterized secondary standard.
14.Written procedures must be established and followed for chromatography analysis.FDA required complete data in laboratory records, which includes but is not limited to notebooks, worksheets, graphs, charts, spectra, and other types of data from laboratory instruments.
15. Any falsification or alteration of data or records must be fully investigated under the CGMP quality system to determine the effect of the event on patient safety, product quality, and data reliability. & necessary corrective actions to be taken to determine the root cause. FDA invites individuals to report suspected data integrity issues that may affect the safety, identity, strength, quality, or purity of drug products at DrugInfo@fda.hhs.gov.
16. Personnel involved in the Processing, testing & performing the activity must have the education, training, and experience, to perform their assigned duties & to prevent and detect data integrity issues.
17. All the records or data whether it is generated through computerized systems or electronic form or paper are subject to FDA inspection. example an email to authorize batch release is a CGMP record that FDA may review & firm must allow to review such type of documents.
18. In order to identify data integrity lapses which can can influence CGMP-related or drug application data or can affect the quality of the drug product the firm may appoint third-party auditor. Firm also may include improvements in quality oversight, enhanced computer systems, and creation of mechanisms to prevent recurrences (the fact of occurring again) and address data integrity breaches.
As we know that water is the most essential part of different pharmaceutical preparations & is used for the cleaning of machines, equipment’s and other accessories during manufacturing hence directly & indirectly it plays an vital role in building of product quality.
Why Water System Validation is Important :
1.The purpose of carrying out water system validation is to assure that the treatment process produces a high quality of water consistently.
2. Water system validation is mandatory in order to study the reproducibility, consistency & effectiveness of water system.
3. Regulatory Guideline requirements
4. In order to achieve desired chemical and microbiological quality as per international guidelines.
5. Validation is a complete documented evidence which gives the surety that any specified process consistently gives the end product having predetermined quality parameters and specifications.
6. Establishing the reliability of pharmaceutical water purification, storage, and distribution systems requires demonstrating control of the process through an appropriate period of monitoring and observation.
Water Validation different Steps :
Pharmaceutical water treatment system validation consists of three steps which are: DQ (Design Qualification) IQ (Installation Qualification) OQ (Operational Qualification) & PQ (Performance Qualification)
DQ (Design Qualification) :
1. It includes all the information about various components of water treatment system.
2. It contains complete schematic diagram of mechanical, electrical and water flow in order to verify the appropriate installation.
3. It defines the purification units, safety of the system, control devices & alarm systems.
4. Specify the sampling plans and sampling point for microbiological and chemical testing, describe sanitization methods, define method of analysis and data plotting.
IQ (Installation Qualification) :
1.Installation qualification gives surety and proof that the water system has correctly installed & supplied & meets
2. It involves the development of Installation qualification Protocol, an inspection & test plan for water system.
3. It is necessary to document and certify all the installation parameters prior to perform operational qualification.
4. For the installation qualification of water system, key elements are : Verification of utilities required including compressed air, steam, electricity & feed water.
5. All these utilities must be checked thoroughly when performing installation of system.
6. All the controlling instruments must be calibrated and certified as per written procedures that they are accurate, precise, selective and specific.
OQ (Operational Qualification)
1.It consists of various inspection and tests in order to verify the reliable operation of equipment, system controls and alert.
2. It is complete documented verification of the system that it works throughout the process as per operating ranges consistently.
3. OQ check the operation of water system to provide sufficient quantity of water with specified high quality water, to maintain parameters like temperature, pressure, flow, TOC, endotoxin, pH, conductivity and microbial level.
PQ (Performance Qualification) :
1. When water system has operationally verified, performance qualification step comes.
2. It includes variety of tests designed in order to verify the consistent satisfactory system performance.
3. It is carried out by performing the necessary product test and intermediate test of the process to demonstrate reliable and accurate performance.
4. PQ documents that water quality consistently and continuously meets the predetermined required specifications
Water Validation Testing Phases :
Complete water system validation requires 1 year long time because of possible operating problems, maintenance errors which might occurs during this period, equipment failure etc. One more reason for such long time is to determine the seasonal change on the microbial quality of feed water and to determine the procedure of system sanitization effectiveness against microorganisms.
Water system validation has been categorized into 3 phases: Phase I, Phase II and Phase III.
Phase I Validation :
1. This is preliminary phase and requires a 2 – 4 weeks (14 days minimum) testing period in order to monitor the system deeply.
2.The system is continuously operated in this phase without failure & extensive and frequent sampling is carried out with testing from various locations .
3. Microbiological and chemical testing is performed according to the defined plan.
4. Phase I finalize the sanitizing, cleaning and maintenance procedures along with operating ranges development.
5. Before the end of phase I, system is initiated to operate with some stress or tense conditions like start of system after failure of power or start up after emergency system shut down. System is simulated to operate under normal situation of maintenance like start up of system after regeneration of resin, filter changing, ozone generator failure etc. & in the last water system (Standard Operating Procedure )SOP’s produced.
Phase II Validation :
1.This phase is continuity of previous phase i-e phase I, it carries the sampling plan same as previous phase plan & it also facilitates the monitoring of system for 2 – 4 weeks (30 days) period.
2. In this phase, development of refined SOP’s after phase I completion is done.
3. During phase II, manufacturing can be done with that water.
4. This phase describes that the water system is within predetermine ranges and under control.
5. At phase II, testing also assures the continuous persistent and steady production of required quality and quantity when the water system as per (Standard Operating Procedure ) SOP’s operated.
Phase III Validation :
1.In this phase sampling locations and frequency reduced as compared to previous phases.
2. Phase III represents that the water system shows reliable under control attainment over such a long time period & Phase III typically runs for one year after the satisfactory completion of phase II.
3. Manufacturing can be done during phase III & Feed water seasonal variations also evaluated & monitored in this Phase.
4. Complete microbiological and chemical analysis must be carried out in phase III and results are required to be presented in graphs using computer imitations.
5. Whole validation report should be compiled, written, reviewed and approved as per company’s standard procedure.
6.chemical & microbiological analysis like pH , conductivity, Total organic carbon (TOC) & total bacterial count shall be done through out the above phases .
Post Validation Monitoring of Water :
1. It comprises of routine check and balance of the water system, normal sampling and routine analysis & maintenance of equipment.
2. All the phases should be monitored in order to assure that the required desired conditions are satisfactorily set as specification.
3. All these checks should be clearly documented in the respective log book as well as in the reference validation protocol & Report
4. Any deviation or change from this procedure should be documented and investigated.
5. There must be a written procedure or program for maintenance of equipment part should be defined in the protocol.
6. The procedure should have all the details of items required to check calibration and maintenance frequency.
Re-validation of Purified water System :
Re-validation is important which can occur due to various condition
Periodic Re-validation & Re-validation after any changes
Periodic Re-validation :
over certain period of time water system need to be change & Periodic Re-validation is done to evaluate the impact of the change.
During periodic Re-validation some areas of water system should undergo changes like Standard Operating Procedure, Specification & calibration etc.
Re-validation after any changes :
1.It should be done to evaluate the quality & system of water after any changes.
2. Addition or deletion of any parts or utilities to the existing water system
3. Addition or deletion of any user point or expansion of distribution system
4. Any major change in the process equipment or any maintenance work performed after any major breakdown
Good Laboratory Practices (GLP) was first introduced in New Zealand and Denmark in 1972, and later in the US in 1978. It was followed a few years later by the Organization for Economic Co-operation and Development (OECD) Principles of GLP in 1992 & the OECD has since helped promote GLP to many countries.
GLP is not only limited to chemicals but also it applies to medical devices, food additives, food packaging, colour additives and other non-pharmaceutical products or ingredients as well.
What is Good Laboratory Practice (GLP) :
Good Laboratory Practice contains a set of principles that provides a framework within which laboratory studies (Activities) are planned, performed, monitored, recorded, reported and archived. GLP help assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be confidence upon when marking risk/safety assessment.
Why GLP is Important in Pharmaceuticals :
Good Laboratory Practice contains different principles which are designed to ensure and promote consistency, quality, safety, reliability and integrity of chemicals during non-clinical and laboratory testing.
Basic Rules of GLP :
1. Make sure to have the correct written instructions before starting a task. 2. Do not carry out task for which you have not been trained. 3. Keep records of information, results and actions taken. Make clear accurate records of what was done. 4. Check that the instrument/ equipment/material used are clean, calibrated and correct ones as per procedure.
5. Always notify if labels are seen either detached or appear to incorrect or are in wrong place. 6. Never remove a label which has been incorrectly applied and never stick a new label over an old one of the same type. If label is incorrectly affixed strike it off, sign and paste new correct label adjacent to it
7. Clean the glassware drying oven, refrigerator, walk in chamber incubators, water bath of the instruments like dissolution tester, disintegration testers etc, used in the quality control laboratory as per the procedure. 8. Clean the work benches after completion of work or at the end of the day whichever is earlier and keep the respective specification, General test procedure (GTP), Standard test Procedure (SOP’s) etc used back to the designated place. 9. While closing the Quality Control Laboratory, ensure that all water taps, instruments (which are not running), equipments, computers are put ‘OFF’. Put off the lights, AC’s and closes the department.
Premises and Utilities :
1. Maintain the laboratory and its premises clean.
2. Keep work benches of laboratories clean and tidy all the time.
3. Keep the samples, standards, laboratory reagent, apparatus, accessories and records at adequate and suitable storage space.
4. For analytical preparation wherever water is to be used, use purified water for chromatographic analysis like HPLC, GC, etc. use HPLC grade water or water generated by Milli-Q system.
5. The utilities like compressed air, vaccum required for the functioning of laboratory should have identification mark.
6. Maintain temperature and humidity record as per respective procedure wherever applicable.
7. Follow the procedure in case access control system is to be followed where restricted entry is necessary .
8. In case of hazardous and poisonous materials, keep it at adequate storage area/facility with lock and key to avoid misuse. Also keep reserve sample, stability sample, laboratory standards in lock and key.
9. Use eye washer, water shower, first aid kit etc. in case of emergency which may arise during operation & Always identify the location of emergency exit in the laboratory for exit during emergency
1. All personnel prior to employment should be periodically re-examined for medical fitness. The Quality Control Manager should ensure that the personnel are medically fit to carry out the job.
2. Personnel suffering from an infectious disease or having open lesion on the exposed surface of the body should not engage in activities that could results in compromising the quality of analysis. 3. All employees shall be instructed to report about their illness or abnormal health condition to their immediate supervisor so that appropriate action can be taken. 4. The job responsibility should be assigned according to competency of the person and it should be timely revised for addition or deletion of responsibilities assigned previously.
5. Smoking, eating, drinking,chilling or keeping plants, food,drinks and personnel medicine should not be permitted in laboratories area, where they might adversely influence the product quality. 6. Personnel should wear clean clothing (company uniform)suitable for activity with which they are involved and this clothing should be changed when appropriate. Personnel should strictly follow entry/exit and gowning procedure. 7. While handling hazardous chemicals and while performing sterility, microbiological analysis, procedure of change of clothing and use of personnel protective equipment’s and safety appliances should be strictly followed.
8. Never handle any chemicals, raw materials intermediate & finished, unpacked product with bare hands. Always use the appropriate hand gloves while handling the same.
1. Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operation that the employee performs. Training should be given on both the theory and practice of the work being undertaken in a particular area, as well as relevant ‘on-job’ training.
2. Records of training must be maintained. Training should be periodically accessed. All staff, including new staff and existing staff should be given basic training on Good Laboratory Practices during induction and at regular intervals subsequently. This training programme should be periodically updated.
Instruments / Equipments / Accessories :
1. The analytical instrument shall be house in dust free environment and whenever required, conditions of temperature and humidity shall be maintained at periodic checks of temperature and humidity be made and recorded.
2. All instruments / Equipments shall be qualified properly through IQ, OQ and PQ activities after receive in the laboratory.
3. Instruments requiring calibration shall be calibrated at regular intervals and records of such calibration or maintenance be maintained and there shall be written instruction in the form of Standard operating procedures for the operation.
4. Other equipment / accessory such as burette, pipette, volumetric flask, weight boxes, thermometers, etc, shall be thoroughly checked for accuracy of calibration before acceptance for use.
5. Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. Software should not be left opened and unattended to avoid misuse. After use, save the data and close all operating system properly and then switch off the computer system.
6. Water from instrument / equipment (e.g. Dissolution, DT, Sonicators, etc.) should be changed regularly. When Instrument / equipment is not in use for longer period (e.g. breakdown) water should be removed and the instrument /equipment kept dry.
Validation / Verification of Analytical Methods : 1. A written protocol should be established that specifies how Validation /Verification will be conducted. The protocol should be reviewed, approved and authorized by the designated authorities.
2. A Validation / Verification report should be prepared, summarizing the results obtained, and drawing the appropriate conclusions, including recommendation for changes if any, based on the study.
Testing and Reporting :
Sampling should be done in accordance with approved written procedure
Sampling staff should trained for sampling activity and should have the knowledge of the nature of the samples to be handled and should refer respective specifications for the same
Sampled containers should be adequately labelled and should have information for traceability
Testing and Reporting :
There should be written procedure for testing materials and products at different stage of manufacture, describing the methods and instruments / equipments to be used
There should be written procedure for testing materials and products at different stage of manufacture, describing the methods and instruments / equipments to be used & Specification should be available for every product / item .
Testing should be done as per approved specification. The results obtained should be checked for compliance against specification. All calculations should be checked. The records of testing should be maintained.
Use clean spatulas or butter papers for transferring and weighing samples .
Attach all relevant analytical raw data obtained from instruments such as Analytical Balances, High Performance Liquid Chromatograph, Gas Chromatograph, UV-Spectrophotometer, IR-Spectrophotometer, Polarimeter, Refractometer, Potentiometer, Bulk Density Apparatus, to the record of analysis / calculation sheet.
In case of analysis of temperature sensitive material stored at 2-8°C or in freezer (between -25°C to -10°C) .
During analysis, if any abnormal or unexpected event or out of specification results occurs, address the same using a Incident Report or out of specification report & analysts shall report all Incidents and OOS to the Supervisor or Quality Control Manager as soon as possible.
Stability Studies :
Stability studies should be carried out to obtain evidence on how the quality of a drug substance or drug product varies with time under the influence of factors such as temperature, humidity and light and enables establishment of recommended storage conditions, retest periods or shelf life for drug substances or drug products.
A schedule should be designed to monitor the stability of each product .
Out ofspecification or significant a typical trends should be investigated. Product failures should be promptly reported to technical head, regulatory affairs, R and D, quality assurance and customer, (if applicable), for necessary action. The possible impact on the batches distributed in the market should be considered.
Asummary of data generated should be written and maintained. This summary should be subjected to periodic review.
Chemicals , Reagents, Glassware and Analytical Standards :
All reagents and solutions in the laboratory shall be properly identified with a label. Validity should be provided as appropriate for analytical reagents or standard solutions prepared and should be indicated on label together with specific storage conditions.
Check the validity period of chemicals before use & standards and solutions should be labelled
All the solutions, solvents dispensed and solvent waste collected in vessel / beaker should be covered entirely with appropriate cover.
The glassware should be examined before use for cleanliness and damage; do not use cracked, chipped or any other defective glassware.
Specifications, instructions, procedures and records must be free from errors and available in writing.
Documents should be approved, sign and dated by appropriate and authorized persons.
Records should be made or completed at the time each action is taken and in such a way that all significant activities are traceable.
Good Documentation practices should be followed during entire documentation.
Good Laboratory Practices (GLP) in terms of A to Z :
Note books/Nose masks
Entry & Exit
Results of Not following GLP in Laboratory :
Accident/Incident & Health Hazards
Wrong/error in volume or weight measurement which may leads to wrong results.
May leads to Instrument errors/Malfunctions
Contamination of sample, reagent & solvent which may affect the product quality to be tested.
Waste of time due to investigation of unexpected cause.
Increase cost due to repetition & investigation
Due to wrong result it may affect patient safety.
Regulatory agency may take action results in warning letter, import alert etc.
No evidence or documented proof of data generated
Everyone makes mistakes that’s why GLP is needed. GLP principles are a good idea even if you are not required to follow the standards. There are some simple rules such as : Say What You Do (with written standard operating procedures), do what you say (follow the procedures), be able to prove it (with good record keeping).
The principles of good laboratory practice (GLP) is to support the development of quality and validity of test data used for determining the safety of chemicals and chemicals product.
Hence GLP aims to decrease the occurrence of mistakes or mix-ups through large and specific labelling requirements.
So every analyst those who are working in Quality control or in other testing laboratory should follow GLP.
Validation is a concept that has been develop gradually since its first formal appearance in United States in 1978. The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in 1979 in USA, to improve the quality of pharmaceuticals. In 1996 GMP guidelines were published by WHO for the validation of manufacturing process
What is Validation :
Validation is the process of establishing documentary evidence of the consistency of any process or System & it is the collection and evaluation of data from the process design stage which establishes scientific evidence that a process is capable of consistently delivering quality product.
Why it is Important in pharmaceutical for any System or Process:
Regulatory Requirement (GMP,FDA,MHRA,TGA & other regulatory agencies)
To confirm the process design as capable of reproducible commercial manufacturing & make the process better understood.
To identify Risk/Worst Case assessment.
To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement.
Quantitatively (quantity of something rather than its quality) determine the variability of a process and its control.
The variability within and between batches can be evaluated.
Safeguard and process against sources of variation which may not have been identified during the original process development.
The reason to optimize and validate pharmaceutical productions and supporting processes and cost reduction.
Decreases the chances of the product failure & assures the smooth running of the process.
Investigate the deviations if any from established process & Analytical parameters.
Result obtained in the validation helps to take decision for the manufacturer regarding repeat the batch manufacturing
Validation is legible through the documentation establishment and it guarantees a manufacturing process with assured product quality.
Deep study & understand the system & equipment are made possible due to validation.
What is Worst Case-It is a set of conditions encompassing upper and lower limits and circumstances, including those within standard operating procedures, which pose the greatest change of process or product failure when compared to the ideal conditions.
Different types of Validation in pharmaceuticals :
Water system, cleaning of equipment, manufacturing process, HVAC System, analytical method, computer system, water system and compressed air are related to system and process which are required. All new system, equipment and process must be validated before routine manufacturing use.
Why Three consecutive batches taken for Validation :
What is Consecutive : Consecutive comes from the Latin consecutus, meaning following closely with no gap or following one after another without interruption.
Why three batches to be taken for Process validation this is a common question which will come in everybody’s mind while executing or performing the activity.
1.Actually neither FDA or nor any regulatory guidelines says about the maximum numbers of batches to be taken for validation. The number of batches to be taken under validation depends upon the risk involved in the manufacturing Critical process parameters & critical Quality Attribute so depends upon that manufacturer have to choose the number of batches to be validated.
2.If we will consider less than two batches then the data will not be sufficient for evaluation of and to prove reproducibility of data between batch to batch variation & if we consider more than three batches it can increase the time & cost of manufacturer which usually not preferred.
3.Generally if we will require quality in the First batch, then it is accidental (co-incidental), Second batch quality is regular & third batch quality is Validation or Confirmation.
4. Statistical evaluation cannot be done by considering two points, because two points always draw a straight line so minimum three points required for comparison of data.
5.Therefore for Process as well as for cleaning validation three consecutive batches are preferred by the manufacturer.
Validation allows us
to focus on our everyday business operations of making and selling quality
products that also comply with regulatory requirements such as the FDA,
Schedule M, GMP, USFDA, MHRA, WHO etc. The industry which has adopted a
lifecycle approach to the product development, validation and modern risk
analysis tools can control critical process parameters.