“Effective CAPA System”- An assurance to “Acceptable-State-of-Control” of QMS

“Corrective Action” was the term first incepted by the US Government during the second world war to address nonconforming material in “Military Standard 1520”. Primarily, the focus of military standard was to standardize the method on nonconforming material and their dispositions, subsequently retitled as “Corrective and preventive action” (CAPA) and now recognized to be a fundamental prerequisite in order to ensure healthy functioning of “Quality Management system’.

CAPA’s requirement is well delineated in numerous ISO business standards as well as in GMP guidelines, such as; “ICH-Q7 guidelines on Good manufacturing practice guide for active pharmaceutical ingredients Q7 ” and “US-Food and drug administration department of health and human services, 21 CFR Part 211-current good manufacturing practice for finished pharmaceuticals”. However, the noteworthy concept of “CAPA” emerge with the inception of “USFDA- Guideline on “Guidance for Industry-Quality Systems Approach to Pharmaceutical CGMP Regulations released in Sep-2006” followed by various ICH guidelines namely, “ICH-Q8 on Pharmaceutical Development”, “ICH- Q9 on Quality Risk Management” and more importantly “ICH-Q10 on Pharmaceutical Quality System” came into effective from June 2008. 

CAPA is regarded a life cycle approach with the coverage of all four phases of product as per “ICH-Q10 -Pharmaceutical Quality system (PQS)”, in supplement to this, “USFDA- Guideline on “Guidance for Industry-Quality Systems Approach to Pharmaceutical CGMP Regulations” describes the CAPA as a well-known cGMP regulatory concept that focusses on investigating, understanding, and correcting discrepancies while attempting to prevent their recurrence.

CAPA’s Regulation for Pharmaceutical regulated Industry:

•  ISO 9001 & 13485: Quality Management System, clause 8.5.2 & 8.5.3.
• CDSCO-India: Schedule M- good manufacturing practices and requirements of premises, plant and equipment for pharmaceutical products, clauses 15.1 to 15.3 & 24.2.
• ICH-Q7 on “Good manufacturing practice guide for active pharmaceutical ingredients”, clause 2.41, 2.50, 2.51, 11.15 & 15.12.
• 21 CFR Part 211-current good manufacturing practice for finished pharmaceuticals, clause 211.22 & 211.92.
• U.S. Food and Drug Administration’s regulation governing medical device manufacturers quality systems: 21 CFR Part 820.100.
• USFDA: Guidance for Industry-Quality Systems Approach to Pharmaceutical CGMP Regulations, clause III- C & D , IV-D (4 & 6) & glossary.
• WHO-Good manufacturing practices for pharmaceutical products: main principles, TRS-961, Annex-3.
• USFDA-Guidance for Industry on “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production”, clause Phase-I (b), Phase-II (a) & V.
• MHRA-Guidance document on “Out Of Specification Investigations”, clause Phase-II & III.
• ICH-Q8: Pharmaceutical development, clause- appendix-I (life cycle management).
• ICH-Q9: Quality Risk Management, clause 1.5, I.3, I.5, II.4 & II.7.
• ICH-Q10: Pharmaceutical Quality System, clause 1.7 (f), 3.2.1 (a), 3.2.2 (Table-II), 3.2.4 (a) & glossary.

Helpful tips to develop an “Effective CAPA system” – ‘3P Model’:

CAPA is a fundamental management tool for Quality System demands the three essential steps as illustrated per below Figure.-2 i.e. effective CAPA system is all about the three stages; “3P- Plan, Process & Product”.

Step-1 -“The Plan” – is to do an effective investigation in identifying the right root cause:

In general, plan is something begins with the end in mind as a product we desire, our ultimate goal to achieve or destination to reach timely and successful manner, which might results into the ineffectiveness or failure in reaching the right destination first in time, if our map or plan is either not available/clear and/or not detailed on “what, why, how, when and where to go?”.

Like-wise, root cause analysis is the first key step in driving an effective CAPA process, approach used for identifying the underlying cause (s) is to understand the basics on how and why an incident occurred so as to conclude the most real root / proximate cause (s) of the problem.

Root cause analysis is typically used when something goes bad and can be described in asking below three basic questions:

What's the problem? This is a typical/problem statement as an outcome of incidents/OOS etc.

Why did it happen?   This can be answered by using the appropriate tools to find out the causes.

What will be done to prevent it? This is typically resultant action points, called as CAPA initiated based on the identified root cause analysis.

Establishing the why? By using appropriate RCA tools:

 There are several RCA tools (such as Cause and Effect Diagrams, Five whys, Cause mapping, brain storming, Fault tree analysis, and failure mode and effects analysis) are available and no single one is fit in providing the solutions for all negative events. The applications and selection of tools comes from the experience, situation and mainly the type of event occurred. Below two tools are discussed here, which are used as most commonly problem solving tools for day-in and out events happens.

Cause and Effect diagram (Fish-bone/6M tool): 

“Cause and effect diagram”, the tool was invented by Dr. Kouro Ishikawa and known as Ishikawa diagram (also known as “Fish-bone” as its structure appears to be like a fish), which connects the dots with the results obtained (called as symptoms) vis-à-vis possible cause (s). This tool is most commonly used at the process and manufacturing operations to provide deeper insight in breaking-down the process into the secondary and tertiary causes so as to reach closer to real and/or proximate cause (s).

5-Why’s Problem solving approach:

“5 Why’s?” is a pragmatic tool to ask “WHY”? And continue to ask until ascertain the right answer on the “root cause of the problem”. The process involves the discussion usually between the cross functional teams comprises with subject matter expert, Manufacturing, engineering, Quality Assurance etc.

Step-2: “The Process”: CA (Corrective Action) & PA (Preventive Actions) assessment and implementation.

An anticipated road-map without converting into the actions has no value as long as it is executed in alignment with the planner. Similarly, root cause analysis has no meaning without converting into CAPAs?. Below is the chronological ways in executing the CAPA’s “PROCESS” effectively.

Correction (Immediate Actions/Dispositions):

The process of corrections includes to bring back the process or product into the desired state or in some cases isolate the event to avoid further damages or impact on the similar or potential product/processes, this may include “repair, rework, or adjustment relating to the disposition of an existing discrepancy”

Corrective Actions (CA):

The process is also known as CA (Corrective actions) begins with the actions identified to eliminate the causes of an existing/detected discrepancy/non-conformity or other undesirable situation to prevent recurrence, below is the chronological process of CA:

• Defining the problem or non-conformity, what?
• Define the cause of the problem, why? i.e. RCA
• Developing an action plan to correct the problem and prevent a recurrence? Identify- CA

Implementing the plan? Execute the identified-CA In specific, CAs are short, immediate actions taken to “correct” or address the existing root cause (s) for each reported deviation/ nonconformance. The actions are designed to eliminate or minimize the potential for recurrence of the deviation/ nonconformance, which are usually initiated (accountability in a formal quality system) or completed prior to closing out of the investigation or proceeding with the next process.  

CA should be trended for the repetitiveness of same problem and its effectiveness be tracked into the quality system with the category of events, examples may include on equipment, product, process, material error etc.

Preventive Actions (PA):

The process is also known as PA (Preventive actions) begins with the actions identified to eliminate the cause of a potential discrepancy/non-conformity or other undesirable situation to prevent such an occurrence, below is the chronological process of PA:

•  Define the potential problem or nonconformance? What(Potential)
• Define the cause of the potential problem? Why (Potential)
• Developing an action plan to prevent the potential problem to avert occurrence? Identify potential -PA
• Implementing the plan? Execute the potential -PA

PA, is the process for detecting potential problems or non-conformances' & eliminating them, these are the longer term actions designed to determine the effectiveness of corrective actions, which mainly focuses on to ensure the “prevention” or occurrence of potential deviations/ non-conformances.

PA should be trended for the repetitiveness of similar potential problem and its effectiveness be tracked into the quality system with the category of events, examples may include on equipment, product, process, material etc. PA are required to be initiated or completed after closure of investigation or corrective actions , which mainly focuses on the ‘system’s’ evaluations and continuous improvement rather than quick fix-up.

Step-3: “The Product”: by ensuring ‘Effectiveness check’.

Effectiveness is the process of establishing something worth or degree to which something is capable in producing a desired “Product”, specifically, “Averting the same/similar problem” in future is the key objective in relations to ‘CAPA effectiveness check’, this may include the verification of plan and process as mapped, how did it work, followings can be considered as criterion to prove the effectiveness:  

• Ensure the completion of CA V/s PA as planned.
• Effectiveness of CA/PA can be based on predefined -number of batches versus period.
• Examine the recurring issues, if any and why? Is it really due to this CA?
• While it is subjective in terms of succession criteria as number of successful batches , this may include further into micro level evaluation on to see the degree of improvement as

              - Is likelihood of event increased or decreased?

              -Is the severity of the problem increased /decreased?

              -Is any new hazard or harm detected?

Determine the impact of learning & succession curve with mitigation plan. CAPA can be considered ineffective –fully or partially, if the actions implemented has not produced the desired “Product” as expected to meet pre-defined succession criterion, which further link to life cycle approach and goes on back to start with the RCA again following the same 3P-CAPA model “Plan , Process and Product” until the desired results are obtained.

CAPA’s – Summary & Conclusion:

To summarize aforementioned discussions, CAPA tool is employed in the entire life cycle of the processes, right from the birth to the retirement of a product/processes, i.e. applied as a life cycle tool from ““product development, technology transfer to commercial manufacturing through product discontinuation”. CAPA works begins in parallel to correct the existing problem, while averting the similar potential problem resulting from the investigations of complaints, product rejections, non-conformance's, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring.

Effective CAPA methodology results in continuous process improvements and helps in enhancing the product and process understanding so as to make the systems and processes robust in getting first time-right quality product.

Author: Sanjeev Kumar Singh

Deputy General Manager - Corporate Quality Assurance at Mylan Laboratories Limited

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