Drug Regulatory Affairs – CTD

Drug Regulatory Affairs – CTD.

Drug Regulatory Affairs in Pharma Industry plays important role as all departments of Pharma product Manufacturing Like Quality Assurance, Quality Control, Production, Microbiology also same as Formulation & Development Department & Analytical Development Department.

Drug Regulatory Affairs comes in last stage of Product Preparation & distribution like after complete & successful manufacturing, packaging & incorporation for stability of  Validation batches.main role of DRA department is act as mediator in between Regulatory authority & Manufacturer of Pharmaceutical products. DRA mainly works on eCTD, CTD, ACTD, Clinical studies, Non- Clinical Studies. now days DRA works on ICH guideline M4 : The Common Technical Document.

As per ICH  Organisation of  The Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human use should be as per given below;


Module 1: Administrative Information and Prescribing Information.


1.1 Table of Contents of the Submission Including Module 1.

1.2 Documents Specific to Each Region (for example, application forms, prescribing information).


Module 2: Common Technical Document Summaries.


2.1 Common Technical Document Table of Contents (Modules 2-5).

2.2 CTD Introduction.

2.3 Quality Overall Summary.

2.4 Nonclinical Overview.

2.5 Clinical Overview.

2.6 Nonclinical Written and Tabulated Summaries.




2.7 Clinical Summary.

-Biopharmaceutic Studies and Associated Analytical Methods.

-Clinical Pharmacology Studies.

-Clinical Efficacy.

-Clinical Safety.

  • Literature References.

-Synopses of Individual Studies.


Module 3: Quality.


3.1 Table of Contents of Module 3.

3.2 Body of Data.

3.3 Literature References.


Module 4: Nonclinical Study Reports.


4.1 Table of Contents of Module 4.

4.2 Study Reports.

4.3 Literature References.


Module 5: Clinical Study Reports.


5.1 Table of Contents of Module 5.

5.2 Tabular Listing of All Clinical Studies.

5.3 Clinical Study Reports.

5.4 Literature References.

SOP on Maintenance and Preparation of Anaerobic Culture Suspension.

SOP on Maintenance and Preparation of Anaerobic Culture Suspension ( Clostridium Sporogenes ).

This procedure is for Maintenance & preparation of culture suspension for anaerobic microorganisms in Microbiology Department.  it includes maintenance of culture & preparation of culture suspension as per Culture Dilution Method.



  • Prepare Nutrient Agar as per Media preparation SOP
  • Pour 5 mL of Nutrient Agar in clean 18 mm rimless test tube.
  • Plug the tube with cotton and wrap the cotton plug with butter paper and label the tubes for type of media, autoclave lot no and date of sterilization.
  • Steam sterilize the media slants, as per the validated autoclave cycle.
  • Place the media tubes under laminar airflow (LAF) at approximately 30º from the surface.
  • Allow the media to solidify.
  • After the solidification of the media slants, 30 to 35ºC for 48 hours for checking of any contamination
  • Streak the surface of the Nutrient Agar with Culture and incubate under Anaerobic Condition at 30-350C for 72 hours
  • Observe for the growth and perform gram staining.
  • Clostridium Sporogenes shall be Maintained as per Annexure


Preparation of Culture Suspension:

  • Prepare Reinforced Medium and Columbia Agar in a conical flask.
  • Reconstitute the media with the required volume of purified water.
  • Boil the media in the water bath to uniformly dissolve the medias.
  • Dispense 15 ml of the media in a clean 18 mm rimless test tube.
  • Plug the tubes with cotton plug and wrap the cotton plug of the tube with butter paper and label the tubes for type of media, autoclave lot no and date of sterilization
  • Similarly prepare normal saline solution (0.9% w/v sodium chloride solution) for harvesting.
  • Transfer 9 ml of the normal saline solution in test tubes and label the tubes with autoclave lot no and date of sterilization.
  • Plug the test tube with cotton plug and wrap the plug with Butter paper.
  • Steam sterilize normal saline solution tubes as per the validated autoclave cycle.
  • After steam sterilization remove the normal saline solution tubes and peptone Solution tubes from the autoclave.
  • Transfer the culture slant and the dilution tubes to microbial limit test room.
  • Prepare culture suspension by washing and scraping the surface of the slant by means of sterile inoculating loop in 10 ml of 0.9% saline Clostridium Sporogenes
  • Transfer the culture suspension in a sterile test tube.
  • Collect the suspension in a sterile test tube.
  • Vortex the culture suspension to obtain a uniform suspension.
  • Carry out serial dilution so as to obtain a culture suspension of 10-100 cfu/ml by following the steps given below.
  • Transfer 1 ml of the suspension to 9 ml sterile normal saline solution – 101
  • 1 ml of 101 Dilution to 9 ml sterile normal saline solution – 102
  • 1 ml of 102 Dilution to 9 ml sterile normal saline solution – 103
  • 1 ml of 103 Dilution to 9 ml sterile normal saline solution – 104
  • 1 ml of 104 Dilution to 9 ml sterile normal saline solution – 105
  • 1 ml of 105 Dilution to 9 ml sterile normal saline solution – 106
  • 1 ml of 105 Dilution to 9 ml sterile normal saline solution – 107


  • Note : For preparation of Clostridium sporogenes microbial dilution add 1mL of immersion oil on the surface of the normal saline solution.
  • Pipette out 1 ml of the each inoculum from last three dilution tubes into sterile petriplate in duplicate and perform Pour Plate Technique.
  • Incubate the Columbia Agar plates of Clostridium sporegenes anaerobically at 30 to 35ºC for 72 hours.
  • Till the observation of the microbial counts preserve all the dilution tubes at 2 to 8ºC.
  • After incubation count the colonies and note the microbial count in the format attached as Annexure
  • Note the dilution, which is giving a microbial count in between 10 to100 CFU/ml.
  • Preserve the previous dilution which is giving 10 to100 CFU/ml. This dilution shall be preserved for microbial inoculum and from this dilution 100μl of the suspension shall be used for testing. Eg., if the 106 dilution is giving microbial count in between
  • 10 to 100 CFU/ml the 105 dilution tubes shall be preserved and 100μl of the suspension shall be used to give microbial count in between 10 to 100 CFU/ml.

Label should be given to each tubes and it should contain SOP No. , Name of Microorganism, strain no, dilution count & due on. ti maintain the documentary records of the same annexes should be added in SOP.

Annexure like – Enumeration anaerobic culture suspension record . culture maintenance record & Innoculum preparation record.


Reference :- British Pharmacopoeia.

SOP on Change Control

SOP on Change control




        • Initiation of a document or modification of approved documents including but not limited to Master Batch Records (MFR/ BMR/ BPR), standard Operating specifications, Method of Analysis, format / Labels, Qualification / Validation Protocols, Stability Protocol, Validation Master Plan, Policies and Guidelines, Site Master File, Change in manufacturing process

        • Planned modification, Major maintenance, removal / decommissioning and inclusion of equipments, utility, facility / building.
        • The Department, by whom the change / modification is initiated, shall first request for change control form from QA and fill up the change control form with brief details of the change and the reason for the same with proper justification.
        • Quality Assurance shall issue a change control form & allocate a change control number according to the nature of change requested.  the numbering system described in this SOP and shall note the number in the change control log.
        • The initiator shall then complete the change control form in all respect elaborating the scope / justification of the change in consultation with concern other department(s) as appropriate the details of these documentation have been describe in the documentation approach  of this SOP.
        • The existing system and the proposed change shall be briefed in the specified sections of the change control (separate sheets can be used, if necessary).
        • The initiator shall also perform the impact analysis in co-ordination with other concern Department(s) and write the recommendation if any as specified in the section of change control form.
        • The Manager of the initiator department should review the change control form and the impact analysis and add any recommendation for a limited number of months based on prior approval of QA. The implementations of preceding years shall also be reviewed in the current APQR.
        • The department Manager is to sign of the change control form and forward it to Quality Assurance for review.
        • Quality Assurance should recommend/ any additional actions if necessary and identify the requirement for comments of other affected department with consultation of Manager Change control then shall forward to other affected department for their comments (Whenever required).
        • If required comments of any department which is available outside the plant including Corporate Quality (CQA), change control shall be forwarded to respective department through scan copy / hard copy / any other communication mode. Signed scan copy should be attached with change control (where required).
        • Change control shall be forward to plant Manager for his / her review and comments.
        • QA shall take the comments of customer / contract giver on respective column of change control form (Whenever required) through scan copy / hard copy / any other communication mode. Signed scan copy should be attached with change control (Whenever required).
        •  QA  shall review the completion status of initiation, impact analysis, comments of other responsible personnel and will sign as reviewed by the change control form and completely filled change control shall forward to Manager – QA / Designee for Approval / Rejection of change control.
        • When the change control is raised for new product / process / equipment impacts on the cleaning validation, process validation and analytical method validation shall be analyzed specifically along with the impact on other Manager ings.
        • The Manager -QA / designee shall review the impact analysis and approve / Reject the change control with addition / deletion of recommendations as appropriate.
        • The Manager -QA / designee shall tick on the Category (Critical, Major & minor) and Approved / Rejected status.
        •  QA  write NA wherever Not Applicable after approval of change control.
        • The Manager -QA / designee shall assess the change(s) and assign the category as follows:

Category “X” – All Minor Changes which are not classified as major.

# Change in non – critical equipment, which will not affect the quality of finished product.

# Any other change that will not affect the registration material and the Quality of     finished product.

Category “Y” – All major changes having effect on the following

#  Registration material (registration application, including supplements etc.

#  Manufacturing process affecting the quality of finished product.

# Control methods and limits used as the basis for release, which is not affecting the quality of the product.

# Product specification, which has been submitted to the authorities.

# Changes in stability specification.

# Changes in the shelf life of finished product.

# Changes in document, which will affect the registration material.

# Change in solvent used for drug product manufacturing

Category “Z” – All Critical Changes are likely to have an impact on the critical process, procedure, product or system and document. These changes are evaluated against the current commitments and requirement which is directly affect the quality of the product.

  • All the recommendations shall be endorsed by the impacted department Manager s and shall be responsible for compliance of the recommendations.

  • The change control form should be submitted to quality Assurance Department within 7 working days from the issue of the change control number, otherwise the change control issuance shall be cancelled and the change control number shall be invalid.


    • The date of implementation of the change / initiation of modification shall be assigned by Quality Assurance after receipt of the compliance reports of the recommendations that are to be complied before the implementation / execution.
    • All the recommendation that are to be complied before the implementation of the change / initiation of modification shall be complied before the implementation /execution initiation date.
    • The change shall be implemented from the implementation date mentioned on the Change control form.
    • All the recommendations of the change control shall be taken care of during and after change / modification. The initiator department and the impacted departments shall be responsible for the implementation / execution of the change and compliance of all the recommendations.
    • Manager Quality Assurance will review the Risk Analysis as appropriate.
    • After compliance of all the recommendations, Quality Assurance department will review the closure of the change control and get the closure approved from the Manager Quality Assurance.
  • CHANGE CONTROL NUMBERING SYSTEM: The change control number should have the 12 digit following details:
    • The change control number consists of following characters format as described below.
    • (——-) ()         (——–)             ()        (——–)           ()         (        )

Dept. Code   Slash Type of   Change Slash   Sequential No. Slash Year of Change.

The first sections (Two characters) are alphabets and are the department codes.

The third character is Dash “

The second sections (4th & 5th characters) are alphabets which indicate the type of change e.g. DC for document change request,

FCR for facility / engineering / area change request,

SCR for system related change request.

Next Sixth character is slash “

Next section (7th, 8th & 9th characters) are numeric indicating the change control number in the current calendar year, which will start from 001 for each functional department.

Next tenth character is slash “

Last two (11th & 12th characters) are numeric representing the last two digits of the current calendar year.

e.g.: QA-DC-001-18 indicates the First change control for Document

Change given in year 2018 for Quality assurance dept.


    • Change control form shall have the change control number dully allotted by QA and received by initiator department, which is responsible for the movement of change control document for subsequent approval.
    • Change control form shall have the following sections as a part of initiation of a proposed change.
    • SUBJECT: This section should describe the details about the change in which documents / facility / procedure change is required. For Example: To revise document Number AAA, Title: BBB.
    • SCOPE: This section should describe the department / equipment / document / process name / along with the scope of change i.e. briefly what the change is about. For Example: To revise document Number AAA, Title: BBB to incorporate test from current pharmacopoeia.
    • REASON FOR CHANGE: In this section the reason / trigger for which the change is required will be elaborated. This section shall explain why this change is proposed at the moment. It may include but will not be limited to, the implication for some other changes, GMP requirements / change in regulations, addition deletion of equipments, adoption of new process / test method / protocols, gap analysis during scheduled revision etc.
      • In this section the existing process / facility / procedures in the documents that are to be changed will be written briefly.
      • In this section the changes proposed correlating with the existing system, document should be written.
      • In this section the impacts on different aspects like Product, Process, Stability Regulatory, Validation / Qualification, Training, Packaging material, documents or any other parameters / aspects should be analyzed on a centralized approach not confining to the particular system / documents which is under change.
      • Impact on specifications
      • Impact on related documents or Standard Operating Procedures.
    • Change control form shall have the date of implementation of change.
    • Change control shall have a date of its final closure along with compliance of all recommendations thereof.
    • All the attachments to a change control should be numbered and addressed / approved properly.
    • Change control format should be completely filled and signed by concerned personnel and then approved by Manager -QA / Designee before execution and Implementation of change.
    • The day the change control is initiated after obtaining a number from QA until the day it is submitted to QA for review, the change control will be considered as dormant.
    • From the day the change control is reviewed by QA and the day it is approved, it will be considered under impact analysis.
    • This cycle from issuance to approval should not exceed 07 working days, failing which the issuance of change control shall be cancelled and the change control shall be invalidated
    • The day change control is approved and recommendations are duly endorsed by the impacted department Manager s, the change control will be considered as approved but not implemented. However the preparatory work for the implementation can be initiated.
    • The change control status will be considered open after the implementation of change until the compliance of the recommendations. This phase of change control will be crucial as failure to comply with any of the recommendations may result in retraction of the change.
    • If recommendation mentioned in the approved change control not implemented / No action taken against the approved change control within one year from the date of approval of change control, then change control shall be treated as cancelled and new change control shall be fill whenever required.
    • The change control will be closed only after compliance of all recommendations and approval by the Manager – Quality Assurance.
    • The closure of change control should be ideally within 30 days from the approval date of change control. If not closed within 30 working day’s initiator department has to submit justification to QA.
    • A log for the change control shall be maintained as per Format for the         keeping the change controls.
    • Quarterly Review meeting for change control shall be held by Manager – QA with Change Control Committee Member to review the progress or closure of change controls.
    • Quality Assurance shall prepare summary of all the change controls on yearly basis, as per Calendar year – From January to December
    • Product specific change control shall be listed in APQR.
    • Change control shall be preserved according to SOP for destruction & storage of documents.


Self Inspection in Pharmaceutical Industry

Why Self Inspection is Important in Pharmaceuticals industry …?


Self inspection is mandatory by Regulatory Authorities like MHRA, EU, and USFDA. It is one of QMS tools to see that Quality of Product is not compromised by any component of manufacturing site.

Self inspection should be conducted to check effectiveness & compliance with Good Manufacturing Practice Principles also to provide necessary Corrective method for the same.

Self Inspection should cover personnel matters, Premises, equipment, Documentation, Production, Quality Control, Distribution, complaints recalls & self inspection all during self inspection. It should be pre- Programmed & Pre –arranged so it will be easy to verify their execution. So what is procedure to perform Self Inspection..?? What is Minimum Requirements to perform Self Inspection…?

  1. Audit Team.


  • QA personnel should prepare list of Auditors from every department with proper technical knowledge of various functions of organization for training & conducting Self Inspection with consultation of QA Head.
  • Auditor team should be cross functional with minimum one personnel of Quality assurance.
  • All the internal auditors shall be inculcating the following features during self-inspection.
  • Internal auditor should be known about the area and systems.
  • Internal auditor should be confine to the scope of audit only.
  • Internal auditor should be trained for the audit.
  • One internal auditor shall be auditing only other department. They should not audit their department.
  • Training shall be given to the auditors in case any new auditors introduced in auditor list or any change in self inspection procedure.
  • Deficiency Shall be categorized is as Follows:-
  • Minor – no significant impact on product quality/safety.

  • Major – significant impact on product quality/safety.

  • Critical – significant impact on product quality/safety surely to have serious & harmful effect on the patient.


  1. Schedule of Audit.

  • QA personnel should prepare Audit plan/Schedule for year of all departments .
  • Quality assurance shall be intimate to respective departments about the scheduled date of audit, persons who will be auditing, audit report submission time, audit report findings to respective departments, time frame for corrective & preventive action for non-compliances and submission of the documents for compliance of observations report
  • QA personnel should lead Audit.
  1. Audit Activity.

  • Audit members shall be arrange the opening meeting with all the concerned and explain the purpose, scope and the methodology of the audit.
  • Audit must be conducted as per specified Check list as per Department Vise.
  • Scope of Audit should be but not limited to SOPs, SMF,VMP,BMR/BPR/MFR/TT/Method Transfer, Change Control, Deviations , Formats, incidents , product recalls, Market complaints, Compliance of internal and external audits, Pest control, Medical, cGMP Handling of materials, Stability, Analysis of RM/PM/FP, Calibration of instrument, Qualification / Validation, Hold time study, Preventive maintenance schedule, Breakdown history of instrument/ equipment.
  • The audit team shall be check & record the audit observations / non-conformances as per checklist and observed non-conformance.
  • Head QA should review audit observations and respective departments should prepare take action on Non Conformance in given time line.
  • CAPA should be provided by concern department.
  • All Observations compliance time line should be given in SOP.


  1. Compliance & Closure of Audit Observations.

  • QA shall close the nonconformance after satisfactory review of documents which is provided by the Auditee department /other different departments or physical verification basis.
  • QA shall be review the effectiveness of the corrective and preventive action in subsequent self inspection.
  • QA shall be closed the audit observation report after completion of all observed non-compliance
  1. Audit by customers/ External Agency/ Regulatory.

  • Non conformance reports of self inspection is only for internal reference and not to be forwarded to any customers / External agency / Regulatory but if any auditors / visitors asked for the reports then only can be shared.
  1. Preservation of Documents.

  • Audit documents should be preserve till mentioned time line.
  1. Frequency.

  • Self inspection shall be perform twice in a year.

Training of employees

Training of employees


                  Every employee of the organisation shall first undergo an Induction Training and then to be trained on his / her area of operation prior to start the work. Induction Training shall also include a visit and understanding of works done in Departments other than their own. An Induction Training Record shall be maintained for the new employee as per the Annexure, Orientation & Induction training record. The training shall be imparted depending on the nature of job and responsibilities and the cGMP training is mandatory for each employee.

  • Training Plan
    • The training needs shall be based on the criticality of the operation performed by the employees working in different areas.
    • Departmental HOD shall identify the need of training for different levels. The training need identification shall be primarily based on technical aspect related to the operational area.
    • One week prior to execution of training, Quality Assurance (responsible for Training) shall circulate a reminder to concerned HOD, so that they can plan accordingly the activities of their employees. Concerned department shall confirm the date of training and shall inform to concern HOD about the date and time of training session.
    • All the respective department training record shall be maintained by HR dept.
    • induction Training should include cGMP / GLP / GEP / GDP
    • also on Job training /Safety Training/Need base/Refreshing  training should be given to personnel
    • Training should be given by level vise as pen there assigned duties.
    •  Also Training of Regulatory guidelines has to given.
  • Selection of Trainer
    • Internal trainer from different departments shall be identified based on his / her qualification, communication / presentation skills, experience, knowledge and expertise or combination of thereof in the different areas of operation.
    • QA shall prepare list of internal trainers, which shall be approved by Head – Quality Assurance The list shall be updated as and when required.
    • Prior to start of the training the participants shall fill their attendance for all types of training .


  • On the Job Training
  • On the job training shall include the training in the concerned and cross functional departments of the new employees and other as identified.
  • On the job training shall be imparted to all the new joiner’s as well as to existing employees by the concerned HOD or his / her designee related to the area of operation. This training program shall include the training related to the specific aspects of an individual’s role including use of equipment, unit operations, safety norms to be followed and adherence to cGMP.
  • The mode of imparting training shall be through SOP’s, Cleaning Procedures, Operating Instructions, Preventive Maintenance Procedures and Practical Assessment wherever possible.
    • Documentation

 The documentation of different types of training shall be done by the departments as mentioned below:

  •  Induction Training                  :           HR / QA
  • On the Job Training                  :           Concerned Department
  • Technical Training                   :          Concerned Department
  • For EU Training                         :         EuDraLex VL- 4
  • Representative from respective department shall coordinate with QA dept. for conducting any training and maintaining the record of the same.
  • Staff Training card of each employee shall be maintained by QA department.

all personnel should have training records updated.



Microbiology is the crucial section of Sterile Pharmaceutical products, it is very Important in Non- Sterile Products.

Microbiology section is divided in following sections;

  1.  Antimicrobial Effectiveness Testing.(USP <51>)(Ph. Eur. general texts 5.1.3) 
  2. Microbial Examination of Non-Sterile Products.( USP <61>,<62>)(Ph. Eur. method 2.6.13./2.6.12)
  3. Sterility Testing.(USP <71>),(Ph. Eur. method 2.6.1)
  4. Bacterial Endotoxin Testing.( USP <85>)
  5. Particulate Matter.(USP <789>)
  6. Evaluation.
  7. Antibiotic Potency Testing.( USP <81> )
  8. Bio-burden Estimation for Medical Devices.(ISO 11737-1)
  9. Environmental Monitoring.(ORA.007 CHAPTER 9)
  10. Rapid Screening Methods.(ORA.007 CHAPTER 10)
  11. Methods of Sterilization.(Ph. Eur. general texts 5.1.1).
  12. SOPs.

All these test can be found in USP & EP/BP And other regulatory & semi regulatory pharmacopoeias.