Quality Manual & Quality Policy in Pharmaceuticals

WFIWhat is a Quality Manual (Quality System Manual / QMS Manual?

A Quality Manual is a document that was first required by the ISO 9001 standard for Quality Management Systems.

How to prepare Quality Manual A Quality Manual is a top-level document that describes an organization’s Quality Management System (QMS).  It can be used both internally (for employees) and externally (for customers and auditors).  It is common for a good auditor to ask to see a Quality Manual in advance of an audit to get a feel for the organization’s QMS.  By looking at the contents of a Quality Manual then an auditor will start to get an appreciation of an organization in advance of an audit

Format for Quality Manual Preparation

This Quality System Manual is a master document, which describes the entire quality system followed at-

This Quality System Manual has been prepared, checked, approved, and authorized by the following:

Prepared By
Checked By
Approved by

Table of Contents of Quality Manual :

1.0 Introduction – Quality Manual
2.0 Quality at _______________________________:
2.1 Quality Policy (Quality Manual)
3.0 The objective of the Quality Assurance Department
4.0 Quality Assurance Department (Quality Manual)
5.0 Documents
5.1 Quality Assurance Procedure
5.2 Site Master File (Quality Manual)
5.3 Master Formula Record (MFR) and Master Packing Record (MPR)
5.4 Batch Manufacturing Record (BMR) and Batch Packing Record (BPR)
5.5 Specification (Quality Manual)
5.5.1 Raw Material Specifications (RMS)
5.5.2 Packing Material Specifications (PMS)
5.5.3 In Process Specifications (IPS)
5.5.4 Finished Product Specifications (FPS)
5.6 Standard Operating Procedure (SOP)
5.7 Validation Master Plan
6.0 Quality Control (Quality Manual)
6.1 Chemical
6.2 Instrumentation
6.3 Microbiology
6.4 Stability Area
6.5 Functions of Quality Control / Analytical QA Department
7.0 Sampling Procedure (Quality Manual)
7.1 A sampling of Raw Materials
7.2 A sampling of Packaging Material
7.3 A sampling of Intermediate and Finished Products
8.0 Analysis (Quality Manual)
8.1 Raw Material Analysis
8.1.1 Release of raw materials
8.1.2 Rejection of raw materials
8.2 Finished Product Analysis
8.2.1 Analysis of bulk sample
8.2.2 Analysis of Final Pack as per the Finished Product Specification.
8.3 Instrumental Analysis
8.4 Packaging Material Analysis
8.4.1 Release of packaging materials
8.4.2 Rejection of packaging materials
8.5 Microbiological Analysis
8.5.1 Purified/Potable Water
8.5.2 Absence of Pathogens (Quality Manual)
8.5.3 Bioburden on Raw Materials
8.5.4 Bioburden on Bulk Finished Products
8.5.5 Sterility testing
8.5.6 BET testing
8.5.7 Viable microbial monitoring
8.5.8 Non-viable microbial monitoring
8.5.9 Personal qualification for the Aseptic area
8.5.10 Other Utility points
8.6 Preparation & Standardization of Volumetric Solutions
8.7 Preparation of Reagents and Indicators
8.8 Handling of  Out of Specification
8.9 Quality Management System documentation: Incident, Lab incident, deviations, CAPA, CCP


CALIBRATION (Quality Manual)

9.1 Calibration of Instruments
9.2 Calibration of Volumetric Flask, Burettes, Pipettes etc.
9.3 Calibration of Measuring Devices
10.0 Reference Standard and Impurities
11.0 Working Standards
12.0 Stability Study
13.0 In-Process Control and Monitoring
14.0 cGMP Records
15.0 Control Samples
16.0 Finished Product Release to Market
17.0 Documentation
18.0 Retention & Destruction of Records
19.0 Quality Audits
19.1 Internal Quality Audit / Self Inspection – cGMP :
19.2 Vendor Audits
20.0 Failure of Quality
20.1 Internal Failures
20.1.1 Yields
20.1.2 Scrap
20.1.3 In-House Destruction
20.1.4 Re-Design
20.2 External Failures
20.2.1 Market Complaints
21.0 Training (Quality Manual)
21.1 Induction Training
21.2 On-the-Job Training
21.3 Training in the course of employment
22.0 Validation (Quality Manual)
22.1 Prospective Validation:
22.2 Concurrent Validation:
22.3 Retrospective Validation:
22.4 Revalidation:
23.0 Process Validation (Quality Manual)
24.0 Equipment Qualification (Quality Manual)
24.1 Design Qualification:
24.2 Installation Qualification:
24.3 Operational Qualification:
24.4 Performance Qualification:
25.0 Validation Policy (Quality Manual)
26.0 Cleaning Validations (Quality Manual)
27.0 Validation of Analytical Methods (Quality Manual)
28.0 Computer System Validations (Quality Manual)
29.0 Revalidation (Quality Manual)
30.0 Utility Services (Quality Manual)
30.1 Water System
31.0 HVAC System
32.0 Preventive Maintenance Programme
33.0 Contract Manufacturing and Testing
34.0 History

1.0   Introduction – Quality Manual:

This document describes the Quality Management System at _________, ________________ always keen to evolve systems to take care of statutory requirements as per national and international regulations to set up stringent Quality Standards for manufactured goods.

2.0   Quality at _______:

____________, have a firm commitment of all our personnel involved in various activities of the company to assure  “QUALITY” of our products at all levels i.e. a firm commitment to market products with the highest “QUALITY”, conforming to the laid down specifications and adherence to cGMP regulations in all operations.  General requirements are maintained for the Factory and Premises as per current `Schedule M’ of the Drugs and Cosmetics Act 1940 and Rules 1945 of the country and the international regulatory requirements are met. Various operations are carried out under appropriately controlled and specified conditions.

2.1   Quality Policy :

<write down/paste the Quality Policy here>

3.0   Objective of Quality Assurance Department:

The overall objective of “QUALITY ASSURANCE DEPARTMENT” is to ensure that: –

    • The desired “QUALITY” is built into the product at every stage of manufacturing (Applicable to Oral Solid Dosage form and Dry Powder injection).
    • The same is retained in the product throughout the shelf life of the product.

4.0   Quality Assurance Department:

The company has a well-trained quality assurance department, staffed by competent technical personnel directly reporting to the management and independent of all other departments. (Functions of Quality Assurance).

5.0   Documents:

Documentation is one of the most important aspects of any organization.

For every activity carried out in the organization, there must be a written and approved procedure. At the Company, each activity has an approved document.

All the original documents are kept in the quality assurance / regulatory compliance department as “master copy”.  Head QA./ head CQ or his designee issues approved photocopies (in form controlled copy) of the documents to the concerned departments for their reference and implementation.

The quality Assurance / Corporate Quality department maintains the following documents:

    • Quality Manual
    • Quality assurance procedure
    • Validation master plan (VMP)
    • Quality management system (QMS) documents
    • Batch Manufacturing Record and Batch Packing Record (BMR & BPR)
    • Raw Material Specification (RMS)
    • Packing Material Specification (PMS)
    • Intermediate Product Specification (IPS)
    • Finished product specification (FPS)
    • Standard operating procedure (SOP)
    • Qualification protocols and reports and calibration reports
    • Validation protocols and reports
    • Internal/external/regulatory audit and compliance reports

5.1   Quality Assurance Procedure:

    • These are detailed documents for the implementation of the quality management system (system procedures).
    • These procedures cover all activities that individually or collectively influence the quality of a product, whether directly or indirectly.
    • SOPs are written, checked by the user department, and approved by the quality assurance / regulatory compliance department.
    • Approved original copies (master copy) of the sops are kept at the quality assurance / regulatory compliance department.
    • The quality assurance / regulatory compliance department issues authorized /controlled photocopies to the concerned departments of the manufacturing units for their reference.
    • The department-specific sops are prepared by the user, checked by the department head, and approved by the site head of quality assurance.

5.2   Site Master File:

    • This document (Site Master File – SMF) describes the details of the site and the activities carried out at the site. It gives the details of the location and the description of the facility and processes carried out for the products manufactured at the site are mentioned in this document.

5.3   Master Formula Record (MFR)

    • For new products, the master formula record (MFR) shall be prepared by R&D. Each product shall have a unique bulk product code for each variation in pack size. MFR shall consist of the manufacturing formula, raw material calculations, general instructions, manufacturing process, in-process checks, and standard yields. For subsequent revisions, MFR shall be prepared by the production department.

5.4   Batch Manufacturing Record (BMR) and Batch Packing Record (BPR):

    • A standard BMR for each batch size of each product shall be prepared based on the current version of MFR.
    • A standard BPR for each batch size of each product shall be prepared.
    • The quality assurance department issues photocopies of the approved BMRs and BPRs to the production and packing department after authorization and allocates batch numbers. The BMR and BPR are controlled by the QA department for issuance.

5.5   Specification:

The following types of specifications shall be prepared by quality control and maintained by the quality assurance department:

    • Raw material specifications (RMS)
    • Packing material specification (PMS)
    • In-process specification (IPS)
    • Finished product specifications (FPS)
    • Stability studies specification

Specifications shall be prepared in three parts

    • General instructions
    • Specification
    • Method of analysis

For new products, specifications shall be prepared by R&D. For subsequent revisions, specifications shall be prepared by site QC and controlled and maintained by site QA.

5.5.1   Raw Material Specifications (RMS) – Quality Manual:

    • For all the raw materials received at the Company, there are written raw material specifications (RMS) approved by the quality assurance department. All the raw materials are analyzed and released by the quality control department in compliance with pharmacopoeial/in-house specifications.

5.5.2   Packing material specification (PMS) – Quality Manual:

    • For all the packaging materials received at the Company, there are written packing material specifications (pms) approved by the quality assurance department. All the packaging materials are tested and released by the quality control department in compliance with the specifications.

5.5.3   In-process specifications (IPS) – Quality Manual :

    • For all the in-process products, there are written product specifications (IPS) approved by the quality assurance department. All in-process products are analyzed and released by the quality control department in compliance with these specifications.

5.5.4   Finished product specifications (FPS) – Quality Manual:

    • Finished product specifications (fps) are of two types one is the release specification and the second is the shelf life (stability)specification. For all the finished products, there are written finished product specifications (fps) approved by the quality assurance department. All finished products are analyzed and released by the quality control department in compliance with these specifications.

5.6   Standard Operating Procedure (SOP) :

    • Standard operating procedures for every activity carried out in the factory are prepared. Approved original copies (master copy) of the standard operating procedures are kept in the quality assurance department/ regulatory compliance department. Qa / rc department issues approved photocopies(controlled copies) to the concerned departments for their reference.

5.7   Validation Master Plan :

    • This document (Validation Master Plan – VMP)describes the details of the qualification and validation policy of the manufacturing site. It outlines the qualifications and validations to be carried out for the facility, process, equipment, analytical methods and utilities along with the schedule of re-validation.

6.0   Quality Control  – Quality Manual:

    • Quality Control is the core functional area of analytical activity. The quality control system includes control of all the incoming raw materials, packaging materials, and intermediate and finished products till they are transferred to finished goods stores for dispatch or distribution for sale.
    • The quality control laboratory is divided into the following sections:
      • Chemical
      • Instrumentation

6.1   Chemical:

Chemical Lab - Quality Manual

    • The laboratory area is well-illuminated, ventilated, and air-conditioned.
    • The working tables are smooth and made with modular laboratory furniture.
    • The walls are smooth and easy to clean.
    • Work involving the evolution of harmful and obnoxious vapors is carried out in the fume cupboard.
    • A separate wash area for cleaning the glassware is provided.
    • Sufficient storage areas for the storage of chemicals and reagents are provided.
    • Sufficient working space for carrying out the analytical work like; weighing, sample preparation, standard preparation, and analysis is provided.

6.2   Instrumentation:

Instrument Lab - Quality Manual

    • A separate, air-conditioned, and well-equipped instrument room is provided.
    • All sophisticated analytical instruments are kept in this area.
    • Wherever necessary standalone personal computers and printers are provided.

6.3   Microbiology – Quality Manual

    • A separate microbiological laboratory is available.
    • The microbiological laboratory has a separate air handling unit (ahu) with terminally mounted HEPA filters to avoid contamination.
    • A separate room has been provided for media preparation and autoclave.
    • The microbiological laboratory has joint-less self-leveling epoxy flooring.
    • Walls are epoxy coated with smooth surfaces, for easy cleaning.
    • Coving is done for easy cleaning and to avoid the accumulation of dust and microorganisms.
    • Microbiological limit testing and sterility testing areas are maintained with the classification of grades C and B respectively.
    • A pass box is provided for the transfer of samples and sterile accessories.
    • The microbiological laboratory has a separate wash area for cleaning of glassware.
    • The microbiological laboratory has a separate room for keeping incubators.
    • Entry to this area is restricted, only authorized persons are allowed.

6.4   Stability Area:

    • A separate stability area is available.
    • The stability area has been provided with stability chambers for storage of samples at 25°c / 60% rh,   30°c / 75% rh, 40°c / 75% rh, and 30°c / 65%rh.
    • Entry to this area is restricted, only authorized persons are allowed.

6.5   Functions of Quality Control

    • All samples are systematically sampled and analyzed and the result of the analysis is reported by following uniform practice as mentioned in SOP “testing of samples and reporting results of analysis” – sop.
    • Following are some of the functions of quality control are:
      • Testing and release of raw and packaging materials
      • Testing and release of bulk, intermediate, and finished products
      • Quality review/stability studies.
      • Calibration of instruments, equipment & glassware.
      • Periodic preparation & standardization of volumetric solutions and preparation of reagents.
      • Validation of analytical methods.
      • Maintenance of reference samples.
      • Preservation and destruction of records.
      • Environmental monitoring
      • Water analysis (PW/WFI/PSG)
      • Culture maintenance
      • Media maintenance
      • Sterility testing
      • MLT testing
      • Bet testing
    • Documentation ( preparation of departmental SOPs, RMS, IMS, FPS, stability protocol, and reports; Environmental monitoring in production areas with the maintenance of trend data; Training of staff; validation support, etc.)

5.0   Sampling

    • Sampling is a process of collecting a representative portion of material from a batch.
    • To check whether a batch of raw material/packaging material/ finished product conforms or not with the specifications prescribed for the same, it is necessary to test the same.
    • It is impracticable to test every part of the batch.
    • Therefore, it becomes imperative to draw samples, which are representative of the complete batch from which they are taken.
    • Before going for sampling, the QC officer reviews :
      • The test request form (TRF/GRN) was received from raw material stores.
      • Specification of the raw material.
      • Sample quantity to be drawn.
      • Approved vendor list and
      • Precautions to be taken while sampling etc. Before sampling, the consignment shall be re-verified for `physical damage’ if any, and label details. If found satisfactory, sampling shall be executed. If found not satisfactory, material shall be shifted to the `rejected area’ for returning to the party or for destruction. A sampling of raw materials and packaging materials is carried out as per the procedure given in sop: “sampling of raw materials” and sop: “sampling of packing materials” respectively.

In the case of bulk/finished products, the IPA officer reviews:

    • The “Test Request Form (TRF)” for bulk or finished product samples from the concerned production department.
    • Sample quantity to be drawn.
    • Precautions to be taken while sampling etc.
    • Sampling is to be carried out as per sop.

7.1   Sampling of Raw Materials:

    • On receiving the TRF from raw material stores, the quality control officer enters all the details regarding the consignment in the register for `the analytical reference number (A.R. No.) And does the sampling of the consignment as per the procedure described in sop: “sampling of raw material” to affix the `under test’ labels on the sampled container indicating the date of sampling and signature of the quality control officer. ‘sample for analysis’ label with all the details is affixed to each container in which sample is collected. For active ingredients, sampling is carried out from all the containers individually. For excipients, the sample shall be taken based on √n+1.

7.2   Sampling of Packaging Material:

    • On receiving material the request from packaging material stores to QC, the quality control officer does the sampling of the consignment as per sop: “sampling of packing materials”. While sampling qc officer observes the physical appearance and cleanliness of the consignment.

7.3   Sampling of intermediate and finished products:

  • A sampling of bulk: After receipt of ‘the test request form (TRF) for bulk from the concerned production department, a bulk sample is drawn by the IPQA officer, as per sop: “Sampling of Drug Product” after ensuring that the total processing is completed.
  • Sampling of final pack: On completion of packaging the sampling of the final pack is carried out by qa officer as per sop: “sampling of drug product” after receiving the ‘test request form(trf)’ for a final packed product from the production department.

8.0   Analysis:

    • The raw materials and finished products are subjected to chemical and/or microbiological tests as described in the raw material specifications / finished product specifications.
    • The raw material specification and finished product specifications are made taking into consideration pharmacopoeial specifications and in-house specifications, which are developed, by making use of the standard analytical references in literature.

8.1   Raw Material Analysis:

    • The quality of pharmaceutical formulations is largely governed by the quality of the raw materials used in them. Testing of raw materials, therefore, is of utmost importance.
    • The purpose of testing of any raw material is,
    • To confirm that the material is what it is claimed to be.
    • It has the characteristics that will provide the desired quality in the dosage form produced from it.
    • To assure keeping the quality of the final product.
    • A representative sample of raw material is tested for compliance with laid down raw material specifications (RMS) or with the respective pharmacopeia.
    • For all active pharmaceutical ingredients (API), 100% sampling is to be performed & for the excipient square root of the n+1 method is used. Refer to sop: “sampling of raw material”.

8.1.1   Release of Raw Materials:

    • The raw material meeting the laid down specifications is approved and released by the quality control department for use in production.
    • Every container of material released by the quality control department is affixed with an ‘approved’ label with signature and date.
    • Approved labels have the following details:
    1. Item name, Item code
    2. Goods received number (GRN), Batch no. (B. No.).
    3. Analytical reference number (a.r. no.),
    4. Approved quantity.
    5. Container no.,
    6. Assay value. (for API).
    7. Date of release.
    8. Retest due on.
    9. Prepared by.
    10. Checked by.

8.1.2   Rejection of raw materials:

    • Any raw material that does not meet the laid down specifications is rejected by the QC and carries a ‘rejected’ label with signature and date. The material so rejected is then transferred to the rejection area and returned to the vendor at the earliest.

Reports of analysis of raw materials are prepared and maintained by the quality control department.

8.2                 Finished product analysis:

               an important factor in ensuring consistency of quality of a finished product is compliance with the finished product specifications (fps) of the product. Before it is released for sale every batch of product must meet these specifications. Qc analyzes finished products after final packing as per fps.

8.2.1             Analysis of bulk sample:

               to comply with the requirements of schedule ‘m of Drugs and cosmetics act 1940, each batch of a product at the bulk stage is analyzed as per respective in-process and finished product specification and if meets the requirements line clearance is given for the next stage.

               if a batch does not comply with the respective specification, an out-of-specification (oos) is initiated. If there is an oos and found valid then the root cause for failure is identified. The investigation of the oos shall be carried out, as per sop, “handling of out of specification (oos).

8.2.2             Analysis of the final pack as per the finished product specification.

               to comply with the requirements mentioned under rules 74 & 78 of Drugs & cosmetics act 1940, each batch has to be analyzed.

               qc officer prepares reports of analysis and the reports are approved by the QC manager. The reports are retained as a part of the batch manufacturing record. The finished product release is carried out by a department.

8.3                 Instrumental analysis:

Instrumental analysis plays a   very vital role in analysis because of its precision and accuracy in results. Raw materials and finished products at one stage or another need to be analyzed by using instruments. The quality control department at the Company is well-equipped with various sophisticated instruments.  Apart from the instrument manuals, standard operating procedures (sops) are available at the place of work to facilitate instrument operation, calibration, and maintenance. Ups power backup is provided to avoid power failures. The instruments are operated in line with good laboratory practices (glp). All laboratory instruments are calibrated at defined time intervals and serviced as and when required for their effective/intended performance. A record of the same is maintained by q.c. department.

8.4                 Packaging material analysis:

Packaging material plays a very vital role in today’s pharma industry. It is the packaging material, which creates a good, or a bad first impression about the quality of the product. Packaging material is the material that is used to pack the product to maintain the sispq of the product during distribution/sale. In Company, all packaging materials are tested as per respective packing material specification (pms). Most of the tests are physical in nature. Packing and development (p&d) department shall initiate the artwork and forward to scientific department / site qc/production /qa. Based on approved blister/carbonator layouts received from the site and text matter, design provided by the pl holder/contract giver. The final artwork shall be signed by p&d and forwarded to site. The artwork shall be checked head-packing, and head qc.

P&d department shall also send the artwork for approval of contract giver/ pl holder, wherever applicable. The approved artwork, print proof and the color shade cards approved by p&d department are retained by qc department at site. Reports of testing are prepared and preserved by q.c. department.

In case of cartons, literatures, labels, sticker labels, the specimen of item tested is attached to the individual report for ready reference.

8.4.1             Release of packaging materials:


               packaging materials meeting the laid down specifications are approved and released for use in the production by affixing ‘approved’ label with signature and date over it by quality control department. Record of testing of packaging materials are prepared and maintained by q.c. department.

               note: assay value is not applicable for packaging materials.

8.4.2             Rejection of packaging materials:

               if the material does not comply with the specifications, qc shall reject the consignment, and reason for rejection shall be specified on the test request form. The material so rejected is then transferred to rejected area with “rejected labels”. The root cause for rejection shall be identified and based on the findings; communication shall be made to the purchase/vendor. The rejected printed packing materials i.e. Labels, cartons, etc. Shall be destroyed in our premises in the presence of qa personnel after due approval of destruction approval form whereas the unprinted packing materials shall be returned back to the supplier. Records of the same are maintained.

8.5                 Microbiological analysis:

      following microbiological analysis is carried out at lab:

8.5.1             Wfi/purified/potable water: water for injection/purified water/potable water of the water system is sampled from individual user points and tested for total microbial count.

8.5.2             Absence of pathogens:

               raw materials are tested for total count and absence of pathogens as given in their respective monographs. Purified water and potable water are tested for absence of pathogens as per schedule.

8.5.3             Bio burden on raw materials:

               raw material is tested for total microbial count based on tests mentioned in specific monographs or as per customer specifications. 

8.5.4             Bio burden on bulk finished products:

               bulk, finished product material is tested for total microbial count based on tests mentioned in specific monographs or as per customer specifications or in-house specification. 

8.5.5             Sterility testing:

               sterility testing is conducted to detect either viable form of microorganism are present or not in sterile preparations by direct inoculation or membrane filtration methods and performed in an isolator or clean room environment.

8.5.6             Bet testing:

               the bacterial endotoxins test (bet) is a test to detect or quantify endotoxins from gram- negative bacteria using a moebocyte lysate from the horseshoe crab (limulus polyphemus or. Tachypleustridentatus). The most common approach to endotoxin testing is the limulousamoebocyte lysate test (lal test). This assay is based in the biology of the horseshoe crab (limulous). These animals produce lal enzymes in blood cells (amoebocytes) to bind and inactivate endotoxin from invading bacteria.

8.5.7             Viable microbial monitoring is carried out in grade classified area as a, b, c &d as per the sop through settle plate method, volumetric air sampling and surface rinse/swabs.

8.5.8             Non-viable monitoring is carried out in area during qualification through laser particle counter as per the sop.

8.5.9             Non-viable monitoring for aseptic area is carried out on daily basis during operation through laser particle counter as per the sop.

8.5.10          Personal qualification for the persons entering in to sterile manufacturing area is carried out.

8.5.11          Other utility points:

Utility point such as compressed air and nitrogen gas is tested for microbial count from individual user points as per the schedule.

8.6                 Preparation & standardization of volumetric solutions:

               as a good laboratory practice, volumetric solutions are prepared and standardized as per respective sop. The standardized solutions are stored in clean and dry glass bottles.  A label is put on the bottle having details such as name of the solution, molarity factor of the solution, batch no., date of preparation, valid up to and sign of officer along with the date who has prepared it. Molarity factor of standardized solution is valid till it is clear and free from contamination or for one month whichever is earlier. Solution is re-standardized after fifteen days if solution is found to be clear & free from contamination, however the solution cannot be used after one month from the date of preparation. Buffer solutions required for hplc analysis shall be prepared freshly and used immediately, unless and otherwise specified. Records of preparation and standardization are maintained by qc department.

8.7                 Preparation of reagents and indicators:

               as a good laboratory practice the reagents and indicators required for routine analysis   are   prepared as per the pharmacopoeial procedures. Such reagents and indicators are stored in a clean glass bottles having label indicating name of reagent / indicator, date of preparation, validity and sign of the officer who has prepared it.

               these reagents and indicators are valid for three months or as per pharmacopoeia or till it shows any changes in the physical   appearance whichever is earlier. The reagent / indicator preparation record is maintained by the q.c. department.

8.8                 Out of specification

               whenever there is an oos, investigation shall be carried out as per the sop “handling of out of specification”. The preliminary investigation includes identification of obvious error. The retest shall be carried out as per the specification and if the test complies as per specification, oos stands invalid where as if the assignable cause is not identified the extensive investigation shall be carried out for laboratory investigation and manufacturing investigation. In laboratory investigation sampling procedure and integrity of sampling shall be investigated and after identification of the root cause, sample shall be retested and oos can be concluded. In manufacturing investigation review of complete batch processing record shall be done. If the assignable cause is identified particular batch/lot shall be rejected and oos stands valid. Disposition of the batch shall be based on oos conclusion. Based on the extensive investigation and root cause analysis, capa shall be triggered to initiate change control and necessary training to prevent re-occurrence.

8.9                 Quality management system documentation: incident, lab event, planned deviations, capa, change control procedure:

               whenever there is an incident, lab event, planned deviations, investigation shall be carried out as per the sop “handling of incident”, “handling of lab event”, “handling of deviations”. The investigation includes identification of root cause. Based on the root cause analysis, capa shall be triggered to initiate change control and necessary training to prevent re-occurrence.

7.0                 Calibration

               calibration is defined as, ” the comparison of a measurement standard or instrument of  known accuracy with another standard or instrument to detect, correlate, report and/or eliminate by adjustment any variation in the accuracy of the item being compared.” calibration is an essential part of quality control that helps to eliminate errors before they occur.

               proper calibration helps to produce material and products, which meets the laid down specifications, which in turn helps in producing good quality products.  This also helps in reducing cost of the product by avoiding failures; rework expenses, repetition in analysis, etc.

               the objectives of calibration are,

  1. I) to determine the difference or the amount of error between known and unknown readings.

Ii)       adjust the output of the instrument being measured to bring it to a desired value.

9.1                 calibration of instruments:

Our laboratory is well equipped with various analytical instruments useful in pharmaceutical analysis. For efficient work performance, these   instruments   are periodically calibrated and serviced at predetermined schedules as specified in sop “calibration, sop:”

9.1.1             All the instruments are checked for their satisfactory performance.

9.1.2             All the instruments are calibrated periodically as per pharmacopoeia or instrument literature.

9.1.3             Record for calibration and servicing is maintained as per respective sop.

9.2                 Calibration of volumetric flask, burettes, pipettes etc.:

     as good laboratory practice volumetric glassware are calibrated for its verification at the time of receipt. Records of calibration are maintained with the q.c. department.

9.3                 Calibration of measuring devices:

     as a good laboratory practice all the measuring devices like thermometers, hygrometers, temperature gauges, pressure gauges, temperature indicators etc. Are calibrated for their verification at the time of receipt as well as periodic calibration is also done as per current version of respective sop q.c. department maintains records of the same.

8.0                 Reference standardsand impurities:

               reference standards and impurity standards are very important in all types of analysis. Characteristics and suitability for the intended purpose of reference standards and impurity standards are maintained and distributed by the respective pharmacopoeial commissions. In case of non-pharmacopoeial drugs, the reference standards and impurity standards procured from authenticated sources. Reference standards and impurity standards are stored separately as per recommended storage conditions. Record of procurement and consumption of reference standards and impurity standards is maintained by q.c. department.

9.0                 Working standards:

               as reference standards are available only in small quantities they cannot be used routinely for analysis. Working standards are qualified against reference standards and used for daily analysis. Substances, which have been analyzed, released and having highest available purity is selected for preparation of working standard. Assay is determined in duplicate by two analysts and average of the readings is taken as potency for the substance. Working standards are kept in tightly packed vials / container, and stored as per recommended storage conditions. Working standards are valid for one year, if vial opened once its shelf life is nmt 30 days. Records of preparation and consumption of working standards are maintained by q.c. department as per the sop of “laboratory standard management”.

10.0              Stability study:

               stability profile of a drug as a raw material may be indicative of quality, but not necessarily consistent with, its behavior as a part of a finished product (i.e. Formulation). Product stability is significantly influenced by the method or process of formulation and packaging thereafter, along with chemical changes, physically observable changes such as water loss, color etc. Product stability studies are therefore very necessary.

               these studies ultimately aim towards designing not only formulation techniques including packaging, but also bring out optimal storage conditions and useful shelf life. At Company, before launching any product, it is tested for its stability.  Stability studies are also carried out on all the products along with strength, which are put into the market. Stability study is an important function of the qc department which involves periodic review regarding the quality of the products which are already in the market, by carrying out various physical, chemical tests. An annual program for carrying out this activity is made in advance covering the full range of products. Stability evaluation is carried out with objectives like,

  1. I) product shelf life re-confirmation.

Ii) evaluation aspect of shelf life extension /reduction or overages optimization.

Iii) evaluation aspect of shelf life, for a change in product’s packaging design.

12.1              Stability study by testing the product as per approved stability protocol:

               initial three batches of the new product are subjected to accelerated and long term stability testing. Thereafter sample from one batch of each product is kept for stability testing every year (on going stability testing). One sample of each product is collected every year. The periodic evaluation of above collected samples by testing as per respective finished product specification (shelf life specification) is carried out at predetermined intervals, as given in the sop for stability testing. Product specific stability study shall be carried out based on the country / market requirement. Compiled data is submitted to qa for further verification.

11.0              In-process control and monitoring:

               quality of a product cannot be controlled by only testing the product at the end of production. Whenever a product is manufactured, it consumes raw materials and involves processing which may range from simple to very complex. In order to ensure that during routine manufacturing of products, the products produced remain within established quality parameters, a program for in-process control and monitoring has been designed.  

[1] in-process product control checks:

[1.1] routine in-process checks:

Quality assurance staff is involved in the routine in-process checks to highlight any deviation from the specified processes observed and to take corrective action whenever / wherever required. In-process checks as documented in sop are performed every day in each shift by various production departments to check and ensure the quality of the products with respect to (not limited to),  

  • Good house-keeping, line clearance, proper segregation of materials in all the areas, assurance of cgmp.
  • Manufacturing operation as per bmr.
  • Lod, uniformity of weight, hardness, thickness, diameter, friability, dt leak test etc. (for oral drug products).
  • Average weight, uniformity of weight, clarity check, reconstitution time, leak test etc. (for sterile products).
  • Packaging as per the standard packs specification.
  • Overprinting batch details and quality of packaging.
  • Simultaneous and proper recording by production department. The observations are recorded for each and every batch of the product as in-process observation forms of the batch records.

In addition to these, observations like printed packaging materials reconciliation, online rejection, destruction of excess overprinted packaging materials etc. Is performed based on prevailing conditions. Deviations, when noted, are informed in writing to concerned departments for necessary action.  Various sops are being followed for effective in-process operational controls.

12.0              Cgmp records:

               cgmp logs/registers are maintained in the various departments of the company. These pertain to the various entries, records, procedures that are essential as per good manufacturing practices.  Keeping   these   logs/registers up-to-date is the responsibility of the concerned departments whereas; checking these logs/registers for timely entries etc. Is the responsibility of quality assurance, who checks these records routinely at pre-defined intervals.


13.0              Control samples:

               sop for collection, storage and destruction of control / retain sample sop: “management of control sample” of both raw materials and finished products are collected as per sop.  All control samples are stored in separate controlled conditions, in racks provided for them with proper segregation.

  • Store the reserve samples of active raw material for one year after the expiration date and for excipients, six years from the date of release.
  • Finished products control samples are drawn so that they can be examined in future if required through-out the shelf life of the product and is mandatory as per drugs & cosmetics act 1940. Control samples for finished products are collected during packing of each batch of each product and stored for 1 year after its expiry period. The quantity of control samples of finished product collected are such that quantity sufficient for two complete analysis.
  • Record of collection and retention of control samples of finished product is separately maintained by qa department in a ‘control sample register’.

14.0              Finished product release to market

               release of finished product to the market is a very important function of qa department.

               after completion of batch manufacturing and packaging the production department carries out reconciliation and department head checks the bmr and bpr thoroughly and submits to qa department.

               qa verifies the completed bmr and bpr, which includes the  in-process report, finished product analysis reports and after ensuring that the batch is manufactured as per the laid down systems and procedures the batch is released to the market by issuing `batch release form’ to the finished goods stores. If any batch does not comply with any of the following

(i) with the respective finished product specification.

(ii) satisfactory in-process quality checks, etc. 

               investigation shall be carried out and based on the outcome fate of the batch shall be decided. The final authority of release or rejection of any product lies with the head quality assurance or his/her designee. After release of the batch to the market bmr and bpr are preserved product-wise in separate files by qa department, in the record room.

15.0              Documentation:

               documentation is the prime requirement for systematic ‘quality control’ work. All incoming raw materials, packaging materials and finished products are subjected to various tests and measurements detailed out in the respective specifications for compliance before release. The qc chemists  analyze /check the raw materials, packaging materials, finished products and record the details of their findings i.e. Observations, weights, dilutions, readings, calculations and results in the analytical test report.

               all the test reports and certificate of analysis reports are checked by respective section head, approved by qc head. Raw material reports & packing material reports are filed in separate files, qc finished product reports are attached to the respective batch records.

               as a part of good laboratories practices, besides above documentation of routine analysis, qc department maintains following records:

  • Preparation and standardization of volumetric solution.
  • Preparation of reagents.
  • Calibration and servicing records of laboratory instruments.
  • Volumetric glassware calibration records.
  • Sanitization record.
  • Culture maintenance records.
  • Media preparation records.
  • Control samples collection & destruction record.
  • Environmental monitoring records, (classified areas i.e. Production and qc)
  • Procurement and consumption of reference standard.
  • Preparation and consumption records for working standards.
  • List of chemicals, reagents and mediums available.
  • a. report registers.

               each and every work performed by qa /qc officer is documented as glp / cgmp record.


16.0              Retention & destruction of records:

               all bmrs and bprs meant for the regulated market shall be retained at least for a period of five years after certification of the batch by the authorized person and in other cases they shall be retained for a period of one year after expiry of the batch. The records of destruction are maintained by qa department. All the raw material analysis reports are retained for a period of minimum seven years and destroyed thereafter. The record of destruction is maintained by qc department. All the packing material analysis report are retained for a period of minimum three years after consumed and destroyed thereafter. The records of destruction are maintained by qc department. All qms records/ process validation / qualification records shall not destroyed, and maintained in secured manner by qa dept.

17.0   Quality Audits:

    • It is an ideal way to make an independent methodical examination and review of a function with the intent to verify, ensure, and report areas of non-compliance when compared with laid down standards.
    • The quality assurance function needs to include evaluations for current regulatory requirements so that management will have current information on the compliance status of the company.
    • A quality audit is a formal review of a product, manufacturing process, equipment, facility, or systems that conform to expected quality standards.

There are three major types of quality audits:

  • Internal quality audit
  • Vendor audit
  • Regulatory audit

19.1   Internal quality audit/self-inspection – cGMP:

    • Quality assurance officers in their daily in-process rounds, check and confirm that laid down systems and procedures are followed in the company.
    • In addition to routine in-process and compliance to have a complete check and audit of all operations directly and indirectly connected with manufacturing which covers personnel, premises, environment, stores, dispensing, production, packing, quality assurance/quality control  & distribution, internal quality audit is carried out.
    • Self-inspection or internal quality audit is a measure taken to confirm that staff at all levels is following a laid down system and procedure for manufacturing and quality assurance as per sop “self-inspection”.
    • It is designed for evaluation of current practices followed; gap analysis, any cosmetic issues, and follow-up of previous non-compliances, review of the effectiveness of any capa and to suggest corrective actions.
    • Self-inspection is carried out by an individual of the quality assurance department along with team members of another department within the organization having good knowledge of cGMP / Regulatory Requirements & laid down systems & procedures of the company.
    • Self-inspection is independent and impartial. Self-inspection is carried out with an interval of not more than six months.

19.1.6          Advantages of self-inspection:     As self-inspection is independent and impartial it gives a complete idea, of whether laid down systems and staff follow procedures at all levels in each section throughout the company.     It encourages and improves the quality of work in all areas of manufacturing to meet the laid down standards.

19.2   Vendor audits:

    • Vendor audit is a very vital & developing phenomenon in the quality assurance system.
    • Any company following laid down standard procedure for production and quality assurance may have problems in the formulations or stability of its finished product due to raw materials/packing materials used which are manufactured with poor quality systems.
    • Raw materials /packing material may pass initially but may not be suitable on standing.
    • Therefore vendor audit is very vital to assure that vendor is producing goods by following standard laid down procedure.
    • Company has developed system for vendor audit and development of new vendor as per sop: “vendor approval”. The site QA dept, R & D (formulations), and purchase department are made jointly responsible for this activity.

19.3   Regulatory audits:

    • For an organization that manufactures products for the regulatory market, it is mandatory to face inspection from different regulatory body to ensure their products are manufactured as per the standard laid down by their guidelines. All the departments of Company are responsible for all the regulatory audits.    

20.2.1   Market complaints:

    • Market complaints may be received in the form of written communication either as hard copy by courier/fax/telephone or as soft copy through email/sms from a complainant (distributors/retailers / stockiest / field staff/customers/doctors/contract giver / qualified person (QP) / any regulatory authority) regarding the defects in the product quality (purity, efficacy or any adverse reaction) including its physical characteristics, packaging, labeling, etc. Shall be considered as market complaint.
    • Market complaints normally originate from the consumer, trader or the stockiest.

    • The nature of complaints varies from less quantity, physical defects, loss of efficacy; pack defects, side effects etc. On receipt of the complaint, acknowledgement is given to the customer.
    • The complaints are then investigated in detail by quality assurance department with the help of production department.
    • Suitable measures are taken / advised for avoiding recurrence of such complaints.
    • Training is given to all the personnel involved in the work.
    • A suitable reply is sent to the customer. 
    • A complete record of all the complaints, investigation,s and action taken is maintained by quality assurance department.

20.2.2         Product recall:

There are two types: 

  • Regulatory authority initiated recall
  • Voluntary recall
  • Mock recall

Product recall shall be handled as per SOP “Product Recall”

    • Regulatory authority initiated recall:

    • Regulatory authority collects the finished product sample at random from the company or from the market and analyzes it in their laboratories for compliance with label claims & also other physical parameters.
    • In case of any non-compliance, the regulatory authority asks for an explanation and instructs the manufacturer to withdraw the particular batch of the product immediately, it is the responsibility of the QA department to eliminate such recalls by giving proper explanations to authorities if an occasion arises.
    • Voluntary Recall:

    • Voluntary recall is initiated by the company due to any quality problem, which has cropped up during the shelf life of a product.
    • Whenever sufficient data is collected indicating the unsuitability (chemical or physical) of a product or a particular batch of a product for remaining in the market or the consumer’s use the stocks are recalled from all locations wherever distributed by the quality assurance department with the help of the distribution department.
    • This action originates from the quality review data or persistent consumer complaints.
    • The stocks thus received are checked and destroyed after suitable documentation.
    • Mock Recall:

    • A recall was carried out to check the effectiveness of the recall. Mock recall shall be carried out at least for one product, dispatched for sale where maximum distributors are involved.
    • Mock recall shall be performed for the longest distribution chain at least once in two years.
    • During mock recall, traceability shall be performed for at least, one of the raw materials used in the batches identified for mock recall. The depth of mock recall shall be up to the stockiest level only.

19.0   Training – Quality Manual:

Training is a continuous process and an important function of any organization and shall be done as per the written quality assurance procedure “training management”. Training is a must for each and every person in order to develop the required skills, general awareness, and continuous increase in overall efficiency.

The company produces pharmaceutical products. The performance of each and every individual reflects directly or indirectly on the quality of the product manufactured which is very important for the health of the customer. All personnel from operations and personnel from supporting departments play an equally vital role in producing a quality product, so training for all are equally important.

Training is divided into three parts:

  • Induction training
  • On-the-job training
  • Training in the course of employment

21.1   Induction training:

    • Every new employee shall be given induction training over three days with a view to facilitate entry into the organization and to acquaint with the systems and procedures as appropriate.
    • Induction training shall be carried out according to the “induction training programme and training manual”.

21.2   On-the-job training:

    • On-the-job training shall be given to the employees within fifteen days in their respective areas of operation according to the training need identified by department head.
    • Training shall be given on the basis of written protocols of individual departments.
    • During this period, employees shall be trained for usage of equipment, unit operations, safety norms to be followed, sops and sops, validation and calibration procedures, preventive maintenance as appropriate.

21.3   Training in the course of employment

    • Planned training: This shall be done according to the “annual training plan”. This is to be imparted on a periodic basis throughout the year to include the critical procedures. This plan shall be made effective in the month of January each year.
    • Unplanned training: in addition to the training imparted based on the “annual training plan”, training shall be conducted in the following events:
      • Revision of sop
      • Introduction of new sop
      • Changes in the quality system
      • External training
      • In response to market compliant / Deviation / OOS /APQR/ Recall / Returned products / Technical
      • Performance appraisal.
      • Observation of audit etc.

20.0   Validation (Quality Manual):

    • Validation is the collection and evaluation of data from the process design stage through commercial production which establishes scientific evidence that a process is consistently capable of delivering quality products.
    • An action of proving in accordance with the principles of good manufacturing practice that any procedure, process, equipment, material, activity or system actually leads to expected results.
    • Validation is the evidence, which gives high degree of assurance that the product meets the laid down specification.

22.1   Prospective validation:

    • Prospective validation is carried out during the development stage of the product by means of risk analysis of the production process. Then it is evaluated to check whether it may lead to critical situations.

22.2   Concurrent Validation:

    • Concurrent validation is carried out during routine production for sale. This is carried out in case of transfer of products between unit to unit and f&d to unit. The first three production scale batches are covered in concurrent validation.

22.3   Retrospective Validation:

    • There are many processes in routine use in many companies that have not undergone a formally documented validation process.
    • Validation of these processes is possible, by using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do.
    • The steps involved in this type of validation still require the preparation of a protocol, and the reporting of the results of the data review, leading to a conclusion and recommendation.
    • This type of validation exercise is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures, or equipment.
    • The source of data for this validation may include batch documents, process control charts, maintenance log books, records of personnel changes, process capability studies (reflected in a cpk), finished product data, including trend cards, and storage stability results.

22.4   Revalidation:

Revalidation is carried out to ensure that changes in the process/process environment do not necessarily alter product quality or process characteristics.

Revalidation is of two types:

  1. Revalidation after major changes –e.g. Change in starting material, primary packing material, manufacturing process, equipment, in-process controls, etc.
  2. Periodic revalidation – revalidation after the scheduled time interval is performed although no changes have been made to the existing process and to ensure that it is producing the desired product quality.

23.0   Process validation (Quality Manual):

The process is a unique combination of raw material, equipment, and procedures that when brought together and exercised as a whole provides a particular outcome.

Process validation is a documental program that provides a high degree of assurance that a specific process will consistently produce a   product meeting its predetermined specification and quality attributes.(process validation of the company is followed according to the sop “Process Validation”).

Before validating the process the equipment will be qualified.

24.0   Equipment Qualification (Quality Manual):

All critical pieces of equipment used to produce, package, or test the products will be qualified.  Equipment qualification will be carried out as outlined in the equipment qualification protocol as per sop “qualification of equipment “

The validation of facilities, equipment, and services is commonly called qualification. Qualification is divided into four elements i.e. Design qualification, installation qualification, operational qualification, and performance qualification.

24.1   Design qualification:

The purpose of the design qualification is to provide the predetermined requirement for equipment and or instruments for the intended use.

24.2   Installation Qualification:

Installation qualification studies establish confidence that the process equipment and ancillary system are capable of consistently operating within the established limits and tolerance.

This phase of validation includes an examination of equipment design, determination of calibration, maintenance requirements, adjustment requirements, identification of critical elements that could affect the product, etc.

Information obtained from the above-mentioned studies is useful to establish written procedures for calibration, maintenance, product manufacturing, and control of equipment.

24.3   Operational Qualification:

The purpose of the operational qualification is to provide rigorous testing to demonstrate the effectiveness and reproducibility of the process.

This phase of qualification includes checking the functioning of the equipment, switches and indicator lights, cleaning procedures, actions resulting from installation qualification, requalification  (time scales and triggering factors), and testing of processes specific to the equipment.  

24.4   Performance Qualification:

The purpose of performance qualification is to check the performance of the equipment in line with process and key quality attributes.

25.0   Validation policy (Quality Manual):

    • All cGMP/GxP shall be evaluated based on requirements and shall be considered at the time of designing the facility and subsequently shall be qualified before operational use.
    • Major equipment related to process, lab instruments, and supporting utility shall be qualified before use.
    • Validation shall be used as a tool for providing a high degree of assurance that a specific system, process, and facility will consistently produce a product meeting its predefined specifications and quality attributes.
    • A minimum of three batches shall be taken for process validation and cleaning validation.
    • Analytical methods (non-compendial) shall be validated before adopting them for regular use. For the compendial method, pharmacopoeial evaluation shall be performed.
    • The equipment cleaning procedure shall be validated based on the three batches and acceptance criteria shall be defined.
    • Transport procedures shall be validated.

    • Changes impacting SISPQ (strength, identity, safety, purity, and quality) of the product including replacement of the critical parts or any changes in the already qualified equipment that may have an impact on performance shall be subjected to revalidation program through an addendum protocol.
    • Preventive maintenance and calibration shall be carried out as per schedule in order to ensure that the system is in a validated and calibrated state.
    • The existing/legacy system review of the current qualification/ validation shall be performed as an interim qualification review.
    • A report shall be prepared to define further action based on the outcome. As a corrective action addendum to the qualification/validation protocol shall be prepared and executed to mitigate the gap identified. The validation activities that are not performed shall be addressed through an interim qualification review and shall be performed.

26.0   Cleaning validations:

Cleaning validations will be performed on product contact surfaces to assess the effectiveness of the cleaning procedures in –

    • Removing the chemical residues (drug substances, excipients, and or dyes),
    • Cleaning agent(s) and
    • Reducing the microbiological bioburden from processing equipment to acceptable levels. 

The cleaning validation process is to generate data, which can be justified scientifically, to demonstrate that specific cleaning processes consistently perform as expected and produce results that consistently meet pre-determined specifications.

The acceptable storage time and condition of storage for clean pieces of equipment will also be verified to demonstrate that the equipment is free of any microbiological contamination prior to use.                                                                                                                                   

Three types of cleaning procedures are performed at micro as specified in sop “Cleaning Validation”.

The cleaning assessment studies will be based on the cleaning procedure and surface type.  Considerations will be given to critical sites and hot spots.

The criteria for worst-case selection are based on these parameters

    • Type of cleaning procedure.
    • Solubility data of the api used in the drug product.
    • Minimum therapeutic dose of the drug (potency)
    • Toxicity criteria                                                                                                                             

The following conditions/situations warrant cleaning of the equipment:

    • Cleaning between successive batches of the same product.
    • Cleaning between batches of different products.
    • After maintenance Cleaning.
    • Cleaning to prevent cross-contamination. The extent of the cleanliness is evaluated on a case-by-case basis.
    • Cleaning prior to use, after equipment has been cleaned and stored for a prolonged period of time. Duration time and storage condition will be verified as part of the cleaning procedure.

Products will be grouped into product families and a “worst-case” product will be chosen for the cleaning assessment. 

Acceptable limits will be set with the following considerations:

    • The limits established for a given validation must be supported by a scientific rationale.
    • The limits are logical, practical, achievable, and verifiable.
    • Safety factors incorporated
    • Limitations of the sampling method
    • The capability of the analytical methods/instruments (limit of detection and limit of quantification)
    • Batch sizes
    • The quantity consumed by the patient (daily dosage)
    • Difficult to clean due to design and critical sites
      • Cleaning validation shall be evaluated through acceptable residual limit(ARL) /MACO.
      • Practically insoluble in water.
      • 10 ppm
      • High potency (minimum therapeutic dose of the drugs).
      • Toxicity criteria (NOEL)

Analytical methods used in cleaning validation studies will be validated as per individual validation protocol.

27.0   Validation of analytical method (Quality Manual):

Analytical methods used for the identification, or assaying of the purity and or the impurity profiles for drug substances, packaging components, and drug products are validated for reliability, accuracy, and preciseness of their intended purposes. 

All analytical methods used in a validation study are validated.  The analytical methods are validated as outlined in the current USP and the ich guidelines on Analytical Method Validation.  Compendial methods are verified as per individual protocol.

The tests generally considered for method validation are as follows:

    • Accuracy
    • Precision
    • Repeatability
    • Intermediate precision
    • Limit of detection (LOD)
    • Limit of quantification (LOQ)
    • Specificity
    • Selectivity
    • Linearity
    • Range
    • Ruggedness and robustness
    • Stability of the standard and sample solutions
    • Each method of validation has a separate validation protocol and validation report, which is approved prior to any validation activity. The validation reports are issued for carrying out validation.
    • Transfer of analytical methods from pharmaceutical development to analytical services laboratories of importing analytical methods from external laboratories (Sister Companies or Analytical Research and Development lab.) Is qualified with appropriate validation protocols. Records of validation are maintained by the QC department.

28.0   Computer Systems Validations (CSV):

    • Validation of computer systems is of utmost importance as day-to-day activities make extensive use of closed systems to create, modify, maintain, or transmit data.
    • Computer systems shall be validated in accordance with the level appropriate for their use and application.
    • This is of importance in production, engineering as well as in quality control, for those equipment/instruments where the calculation is performed by equipment/instrument and where the setting parameters are printed from the equipment/instruments.
    • All the systems that will be having an impact on the quality of the product (in processing/testing) shall be subjected to validation.
    • The purpose of computer system validation is to ensure a degree of evidence (documented, raw data), confidence (dependability and thorough rigorous achievement of predetermined specifications), intended use, accuracy, consistency, and reliability.

This section describes the approach for validation and overall philosophy with respect to computerized systems; and will include the following – 

    • Identification of the types of computerized systems subject to validation as per sop for computer system validation.
    • A brief description of the validation strategy for different categories of computerized systems as per sop for computer system validation.
    • The test procedures for validation of computer systems.
    • The reporting requirements for documenting the validation exercise and related results.
    • Identification of the key personnel and their responsibilities as part of the validation program.
    • For all critical systems a holistic risk-based approach, considering the risks from the entire pharmaceutical application shall be followed to identify GxP risks and the criteria for assessing the fitness of the system.
    • If the software and systems do not fit readily into the category system then the quality measures, validation strategies, and acceptance criteria shall be determined by applying sound judgment and rationale.
    • Periodic (or ongoing) evaluation/validation shall be performed after the initial validation, which will be done as a part of equipment/system re-qualification.

    • There should be written procedures for performance monitoring, change control, program and data security, calibration and maintenance, personnel training, emergency recovery, and periodic re-evaluation.
    • Aspects of computerized operations that should be considered include (but are not limited to) network; manual back-ups; input/output checks; process documentation; monitoring; alarms, recovery, and shutdown.
    • The life cycle of electronic and paper-based documents may be very similar, however, electronic records can be handled only by systems comprising of hardware and software, which have their own life cycles outlined as below.
    • Programmable logic controller systems play a vital role in equipment automation. A form of man-machine interface, these systems help the operating personnel to devise various sequential programs to control the equipment/instrument/system. Qualification shall be entrusted to an external agency.
    • Revalidation of the computer system is performed as per the sop for computer system validation.

29.0   Revalidation:

    • Re-validation is the repeat of the initial validation to provide assurance that changes in the equipment, process, and/or the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.
    • Revalidation is done for processes and procedures for the reasons stated below. It involves a repeat of the validation process. The validation committee decides the extent of re-validation.

Re-validation is done in the case of:

    • Changes in the physical properties of starting materials may affect the process or product.
    • Transfer of processes to another site (change of facilities and installations that influence the process).
    • Changes in packaging material
    • Changes in the process.
    • Production area and support system change.
    • Changes in the equipment, except when the replacement is of a “like-for-like” type.
    • The appearance of negative trends and the appearance of new findings are based on the current updating of knowledge.
    • Periodic re-evaluation is done on the basis of a review by the validation committee of the following:
    • Master formula and specifications.
    • Calibration records
    • Standard operating procedures
    • Cleaning records
    • Analytical methods, and records of planned preventive maintenance.

30.0   Utility Services (Quality Manual):

30.1   Water system

    • The water system comprises a pretreatment, purified water generation system, storage, and distribution system. Soft water is subjected to RO membrane and EDI to give purified water.
    • This purified water is collected in stainless steel (S.S) 316L tank and distributed through the online UV through a close loop with a recirculation system.
    • The RO-1 and RO-2, storage tanks, and distribution pipelines are sanitized using hot purified water maintained at 80-85ºc for a duration of 60 minutes.

31.0   HVAC System (Quality Manual)

    • The HVAC system is provided to maintain the required environmental conditions for production, quality control, storage, dispensing, and sampling rooms.
    • The entire manufacturing facility is ventilated with an air-control system to create a clean working environment free from contamination. Air supplied to all the areas is filtered. 
    • Additionally, air-conditioned, air is supplied to processing areas.
    • Dedicated air handling units are provided for areas of different classifications and for each production cubicle to prevent cross-contamination. Air supplied to the classified areas is filtered through terminally–mounted HEPA filters.
    • Return air in the processing areas is collected at floor level and filtered through EU4/EU5 and EU7/EU9 filters and finally through terminally mounted EU13 HEPA filters.

The HVAC system is validated to confirm the set parameters as per sop “Qualification of HVAC system

  • Temperature
    • The required temperature in all the areas is maintained at NMT 25°c and NMT 27°c (as applicable) or as defined in the respective sop of environmental monitoring is maintained with the help of air-conditioning system comprising the screw chiller & air-handling units (AHU).
    • The chilled water is produced by the vapor compression refrigeration system and circulated through the cooling coils of the AHU.
  •  Relative Humidity:
    • The relative humidity for all processing areas is not more than 55% and not more than 25% (for aseptic filling) or as defined in the respective SOP of Environmental Monitoring is maintained with the help of ot water circulation in the heating coils of the AHU.
  • Pressure differential:
    • The differential pressure limit is more than 6 mm wc to 25 mm wc (as applicable) with respect to the processing rooms maintained in the processing corridor.

32.0   Preventive Maintenance Program – Quality Manual :

    • The equipment used for processing is maintained in good working condition by following a written maintenance schedule.
    • The responsibility of keeping the machines in working condition lies with the engineering department.
    • A plan for preventive maintenance is drawn by the engineering department for major equipment.
    • The frequency is decided based on the usage of machines, moving parts, age of machines, and past trends.
    • Written standard operating procedures are available for all the activities listed in the plan.
    • The reports of the activities are recorded in forms designed for the purpose.

33.0   Contract Manufacturing and Testing – (Quality Manual):

    • In the case of contract manufacturing for overseas parties, a detailed technical agreement is prepared with the contract giver for the purpose of the manufacturing of goods at the Company, which includes the responsibilities of the manufacturer and the contract giver.
    • A detailed agreement is prepared with the testing laboratory for the purpose of testing the goods on behalf of the Company in case of unavailability of the testing facility wherever required.


Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

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