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Standard Operating Procedure (SOP) for various investigation tools for finding the root causes that enables determination of corrective and preventive action (CAPA).

Handling of Corrective and Preventive Action (CAPA)

1.0   Objective :

• • To describe the procedure describing various investigation tools for finding the root causes that enables determination of corrective and preventive actions.
  • To identify quality issues and GMP issues and to monitor the implementation of corrective and preventive actions.
  • Define a repository system for tracking identified Corrective and Preventive Action (CAPA) through defined quality systems such as (but not limited to.)
    • Deviations
    • External Audit observations
    • Out of specification (OOS)
    • Out of trend
    • Non Conformances
    • Product recall
    • Product Quality review
    • Failure investigation
    • Returned products
    • Market complaints
    • Self inspection
    • Change controls
    • Regulatory issues
    • Any issues that require midterm and long-term corrective and preventive action with formal tracking and documentation, recommendations of executed validation etc.

2.0   Scope :

• • This SOP is applicable for investigation tools and tracking of CAPA’s identified through various              investigations.

3.0   Responsibility :

• • Lead Investigator:
  • Responsible for review and assessment of deficiencies and recommendations for Corrective and Preventive Action (CAPA).
  • Lead investigator shall be supported by Cross functional team.
  • Investigation Team:
  • To identify root cause and to plan Corrective and Preventive Action (CAPA) in case cause is not identified initially.
  • Quality Assurance:
  • Responsible for issue of CAPA numbers and maintaining of Corrective and Preventive Action (CAPA) documents.
  • Head-Quality Assurance/Designee:
  • Responsible for maintaining the Corrective and Preventive Action (CAPA) Tracking log and ensure the implementation of CAPA’s identified.

4.0   Procedure for Handling of Corrective and Preventive Action (CAPA)

• • Approach – Corrective and Preventive Action (CAPA) 

  • To identify and analyze quality system data and information for existing or potential cause which may lead to non conformance.
  • To undertake investigations to find out the root cause.
  • Identify correction, Corrective action and/or preventive actions as required based on the cause
  • Monitoring and tracking of Corrective action and/or preventive actions.
  • Effectiveness verification of quality impacting implemented actions.
  • For Corrective and Preventive Action (CAPA) Procedure, refer the Flow Chart for CAPA procedure.

  • Definitions

  • Correction: Action to eliminate a detected non-conformity. Corrections typically are one time activity but they may be done in concern with corrective action if the problem reoccurs.
  • Corrective action: Action to eliminate the causes of a detected non-conformity or other undesirable situation.
  • Preventive Action: Action to eliminate the causes of a potential non- conformity or other potential situation, which may affect the quality of the product.

  • Corrective and Preventive Action (CAPA) Identification

  • The source of quality problems leading to investigations, root cause identification and CAPA shall be following, but not limited to:

• • Guideline for Investigation and Use of Investigation Tools.

  • Investigation team shall identify and collect the data/ information that are relevant to defining and investing the problem.
  • During investigation, team may find many probable root causes.
  • Team must assess each of the cause and disqualify those not supported by data.
  • Analyze remaining probable root cause (s), and identify those which support investigation.
  • Investigation team shall employ investigation tools and technique mentioned (but not limited to) in Annexure- III.

  • The first technique to be used for any kind of investigation is “Genchi Genbutsu”.

  • The meaning and procedure of this technique is mentioned below.
    • “Genchi Genbutsu” means “Go” and “See” i.e. Go and see for yourself to thoroughly understand the situation.
    • Root cause is identified by using the below mentioned steps.
      • Observe the problem/ situation first hand, personally (not to rely on the report of others).
      • Talk to those at the sharp end (counseling).
      • Explore the contributing visible and invisible factors.
      • Analyze each factor and conclude probability.

  • Second technique i.e. “Brainstorming” may be used to identify the cause of the problem.

  • The details of Brainstorming are mentioned below.
    • Brainstorming: one of the creative problems solving method that allows the people to come- up with suggestions/ ideas that could solve the problem/ situation.
    • A meeting with Cross Functional Team may be called to brain storm on problem/ situation.
    • Relevant people shall ask to think and share their views/ suggest ideas to overcome the problem.
    • All views and suggestions shall analyse to identify the cause of problem.

  • Third technique i.e. WHY- WHY Technique may be used to identify the cause of the problem as per the steps mentioned below.

    • Why-Why Technique: It is questions based technique and shall be used for the each possible factor identify for problem. Question shall ask to the right person in right way at right time and place.
    • Take the problem statement and ask question that “Why did it happened”.
    • For each cause, ask the next “why did not happened”.
    • The cause when identified shall prevent recurrence of the identified nonconformance.

  • Fourth Technique “Six M Framework” (Ishikawa diagram) using fish bone diagram may be used to identify the root cause of the problem.

  • The steps to use “Six M Framework” are given as follows.
    • The Six M i.e. Man (Person), Method (Procedure), Mother Nature (Environment), Materials (Products), Machines (Equipment) and Measurement shall be used as groups or heading of each bone.
    • One by one each group/heading should be considered to find out different alternatives that could be the probable contributory factors.
    • For example, in case of Material (Product), key quality attributes and their impact on each should be considered i.e. Purity, Potency, Strength, Homogeneity, Identify, Stability, Package Integrity etc.
    • In case of machine (equipment) key process variables, critical control points, validation parameters should be considered.
    • In cause of Method (Procedures), examine the changes, procedural compliance and also the unofficial procedures (if any) can be considered.
    • Each alternative should be analyzed and checked for potential relationships between multiple contributory factors.
    • Eliminate alternatives one by one after analysis that shall not be the contributing factors or root cause.
    • Finally list the probable causes and identify the exact root cause or causes among them.
    • From above methodologies identify the root cause(s) for the problem/situation. There can be more than one root cause.
    • ‘Human error’ cannot be a only root cause or a primary root causes for any problem, if ‘Human error’ is identified as cause of the problem then matter shall be further investigated to identify the contributing factors as given below to make an error.

  • Some of the factors (Not limited to) which lead to contribute the human error are tabulated below.

• •  Investigation Process and Corrective and Preventive Action (CAPA) handling:

  • Corrective and Preventive Action (CAPA) shall be planned as a result of the initial evaluation, a documented investigation which will be conducted to determine root or probable cause.
  • An investigation team shall be established to investigate the non conformity or undesirable situation as identified by any of the above quality system.
  • The investigation team shall be a Cross Functional Team including SME members from various departments (like QA, QC, Production, Warehouse, Engineering, HR, and Information Technology etc.
  • Investigation team shall perform the investigation using the tools and techniques defined in Annexure-III (not limited to the listed), investigation guidelines (point 5.4) and investigation checklist (Annexure-VI).
  • Head QA/Designee shall identify the investigators from different departments based on the nature of investigation to be conducted.
  • A person from the concern department as well as QA shall be included in the Investigation team. QA must be a part of investigation team.
  • Head QA/Designee shall identify the well experienced Senior person as a Lead Investigator.
  • Investigation conducted should result into conclusive root cause,
  • however in cases where conclusive root cause cannot be found then most probable root causes shall be assigned. If needed, additional testing of statistical analysis shall be done.
  • If any regulatory issues are involved, the same shall be referred to DRA for their review and suggestions.
  • Based on the root cause found, investigation team shall suggest robust corrective action(s) and preventive action(s).

  • Investigation team also conducts the risk analysis.

  • Investigation team should consider the following during investigation process.
  • Are same type of previous incidents happened and also review the previous investigation CAPA.
  • Investigations routinely expand to include other products, related operations or similar processes.
  • Root causes shall be categorized in to any one or more as per the categories guided in Annexure-VI.
  • Investigation finding shall be recorded in report as defined in the format given in Annexure-IV. (Format for investigation report).
  • Head-QA/Designee shall review the investigation report, Corrective and Preventive Action (CAPA) recommendations and approve or reject the same in Annexure-IV.

  • If Investigation is found not satisfactory by Head-QA, Re-investigation shall be done by CFT as per recommendations of Head QA.

  • The investigation shall be closed before product disposition (Approval or Rejection/Recall) investigation report once approved shall be attached with quality system document (source document) by which investigation triggered.
  • Corrective and Preventive Action Form (Annexure-I) shall be used to initiate Corrective and Preventive Action (CAPA) based on source document listed in above for investigation, impact assessment monitoring of actions triggered from investigation (if any)
  • A Corrective and Preventive Action (CAPA) tracking system shall be used to track all the outstanding CAPA’s identified through different quality systems.
  • Individual quality system track all the actions as per the system defined in the concerned SOP, only outstanding CAPA’s upon stipulated time shall be logged in into the CAPA tracking log.
  • This SOP suggests the following guideline for defining the target dates for closing the CAPA’s.

• • Adequate risk assessment shall be done for all the open actions pending from CAPA’s.
  • Control plans for high risk issues while CAPA’s are being implemented shall be derived on interim basis as and when required.
  • All the open CAPA’s shall be collated, trended and presented as part of Performance metrics and discussed in plant quality review meeting.
  • Certain Corrective and Preventive Action (CAPA) shall be continued whichever products discontinued to check the impact on product remaining in the market as well as other affected product.

• • CAPA shall be log as per the Annexure-II.

  • The Corrective and Preventive Action (CAPA) tracking log shall include information such as CAPA Number, CAPA Description, and Source Document Number, Target Completion and Reviewed by /date.
  • CAPA shall be closed within specified target completion period.
  • Person responsible shall update to Head-QA or designee upon completion of the activity by submitting required documentation.
  • If the Corrective and Preventive Action (CAPA) is not completed within approved target completion date, Alternate TCD shall be taken as per Annexure VII.
  • Implementations of the Corrective and preventive actions shall be reviewed by QA.
  • Upon the satisfactory review, QA shall close the entry in Corrective and Preventive Action (CAPA) tracking Log by putting actual completion date.
  • Any changes to process/operation/equipment/system resulting from Corrective and Preventive Action (CAPA) shall be evaluated and implemented through change control system with appropriate training.
  • All CAPA’s entered in a CAPA log shall be tracked until completion of actions.
  • All the CAPAs shall be monitored on monthly basis by Head-QA or designee.

  • Effectiveness Verification of Corrective and Preventive Action (CAPA):

  • After closure of Corrective and Preventive Action (CAPA) and after 30 calendar days, effectiveness verification of implemented of actions shall be done by QA in co-ordination with cross functional teams.
  • Effectiveness verification shall be done as per Annexure-V (Effectiveness Verification of CAPA).
  • Effectiveness verification shall be done for quality impacting CAPA and shall be decided in CAPA closing section of ‘Corrective and Preventive Action Form’ (Annexure-I) by Head-QA/designee with justification.
  • If any actions required from effectiveness verification, same shall be recorded in Annexure-V and QA shall follow-up to effective implementation.
  • All Corrective and Preventive Action (CAPA) records shall be maintained separately with CAPA log, for easy traceability.

5.0   References – Corrective and Preventive Action (CAPA):

• • WHO Guideline: TRS -908: Annexure-4: Good manufacturing for pharmaceutical product: main
    principles
  • PIC’s Guideline:  Guide to good manufacturing practice for medicinal products (PE009-09) Part-I.
  • The Rules Governing Medicinal Products in the European Union: Volume 4, EUGMP Medicinal Products for Human and Veterinary Use.

6.0   Glossary

7.0   Annexure – Corrective and Preventive Action (CAPA) :

Annexure I : Corrective and Preventive Action Form

Annexure II : Format for Corrective And Preventive Action  Log

Annexure III : Format for Investigation Tools

Click this link for – Investigation Tools used in pharma

Annexure IV : Format for Investigation Report

Format for Investigation Report : _____________________________

Source Document No.(If Any): _____________________________

Problem/Situation Description: _____________________________

Investigation Team Details: _____________________________

Investigation Details: _____________________________

Root Cause/Probable Cause: _____________________________

Impact assessment and/or Risk assessment: _____________________________

Corrective Action: _____________________________

Preventive Action: _____________________________

Comments of Head Operation: _____________________________

Annexure V : Format for effectiveness Verification of CAPA

CAPA Number:

Annexure VI : Format for Investigation Checklist

Investigation checklist will be uploaded soon (under preparation)

Annexure VII : Format for Alternate Target completion date.