Sunday, November 29, 2015

Management of Corrective and Preventive Action (CA-PA)

The concept of Corrective and Preventive Action (CAPA) has doesn’t specifically appear in the older version of Good Manufacturing Practices. CAPA seems to have become popular in the pharmaceutical industry because of its use with medical devices.[ISO 13495:2003 and the FDA’s 1996 Quality System Regulation (QSR) for medical devices, include CAPA. This requirement for medical devices has been extended to the pharmaceutical industry as an expectation by US inspectors.
There are number of points that could trigger CAPA. For example, an investigation, a quality audit, an inspection by national authority, or a complaint. The system should be flexible enough to accommodate these different inputs.
In their 2006 guideline FDA says that the CAPA embodies “Three separate concepts’ including:
·         Remedial corrections of an identified problem
·         Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem
·         Preventive action to avert recurrence of a similar potential problem.
In practice the definitions that the pharmaceutical industry uses for CAPA have been inconsistent
  • Correction:Repair, rework or adjustment relating to the disposition of an existing, discrepancy. Corrections are specifically targeted on a product, material, equipment, system or the like that may have been affected by an unwanted event or incident.
  • Corrective Action: Action to eliminate the cause of a detected non-conformity or other undesirable situation.
NOTE: Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent occurrence.
  • Preventive Action: Action to eliminate the cause of a potential non-conformity or other undesirable potential situation.
NOTE:  Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent recurrence. [ISO 9000:2005]

While there may not be specific US regulatory mandates for CAPA , there is  certainly the expectation that firms take step to prevent problems. For example
US cGMPs manufacturing facilities “must have adequate space to prevent mix ups and to prevent contamination or
As in the European GMPs, “When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust”.
Preventing problem means understanding the vulnerability of a process or operation, the potential sources of harm (i.e., hazards), and how that hazard could be expressed.

GMP expectations

     1. There is a defined process to correct situations that caused or contributed to an incident so the incident doesn’t recur, but also prevents incidents from happening in the first place.

  •  A procedure should exist that describes what initiates a CAPA. This would include reacting to a problem or a “near miss” and also proactively looking for potential problems and taking steps to prevent the incidents from occurring.
  • The CAPA process doesn’t have to be unique for every initiator, such as a complaint or a monitoring excursion. One well understood, robust process that is integrated with different types of events is better.
  • GMPs from different authorities identify some of the elements of CAPA program; ICH Q10 that provides the most expensive and complete escription.
·         GMP references
i)        US: 211.22(a); 211.67(a); 211.192
ii)      CA: C.02.011 #55 ; C.02.015 #7.9.5 ; C.02.029 # 69.1.
iii)    EU: EU 1.4(ix); EU Annex 1,6
iv)    WHO: WHO Annex 3- GMP, 5.1; WHO Annex 3-GMP, 1.2(1)
v)      ICH: Q10, 1.7(f); Q10,3.2.2

    2. CAPA activities are integrated with other quality system elements like Incident Investigations, Complaints, and Change Management.

·         CAPAs could be initiated for many reasons, such as stability failures, quality audits, consumer complaints, incident investigations or risk management plans. All of these system elements should have a defined connection with the CAPA program
·         Because a CAPA may involve a change to a practice or facility, for example, the proposed change must be evaluated and approved through change control.
·         GMP references
i)        US: 211.180(e)
ii)       CA: C.02.012 Rationale; C.02.015 Rationale.
iii)    EU: EU Annex 15,7
iv)    WHO: WHO Annex 3- GMP, 8.1; WHO Annex 3-GMP, 2.1(j)
v)      ICH: Q10, 3.2.1

    3. The most robust CAPA solutions are based on knowledge of the direct and contributing causes and incorporate both controls and mitigations; they do no rely solely on “retraining” personnel.
  •        If CAPA is addressing a failure such as a deviation or incident, organization need to know what caused and contributed to that unwanted event. If the cause of problem remain unknown the CAPA investment could be a waste of time and resources.
  •       Frequently, a problem doesn’t happen because of just one “root cause” often there are several latent or contributing issues that “set the stage” for the failure. A thorough investigation should identify these contributing factors.
  •      If the direct cause or contribution remain unknown the CAPA should emphasize mitigation technique to minimize the impact should the event occur again.
  •      Control and mitigation are terms frequently used in risk management. Control has come to mean prevention, in that if action is taking that affect the probability of the unwanted event from unwanted event from occurring. Mitigation refers to protection, in that the action will minimize the impact or severity of the event should it occur.
  •     One other concept from risk management that applies to CAPA is detection. There may be ‘signals’ that could be detected and acted upon.
  •      As corrective and preventive measures are considered ways should be looked up for ways to have multiple, independent layers. That way if one layer fails, there will be one or two different layers to help “catch” the problem before it becomes significant.
  •    People within the organization should be informed of the event so they are aware that it happened and of the CAPA put in place. This is not, strictly speaking, training.
  •     “Retraining” is rarely and acceptable total solution as a CAPA. If a person has previously been trained and performed the task successfully, that is evidence to show that they can do it. The investigation needs to determine why it was not done at this particular time.

·         GMP references
ICH: Q9, 4.4

    4. The CAPA process includes the evaluation of actions taken to determine their effectiveness.
  •      Once CAPA is put is place it should be determined whether it was successful. This is called “effectiveness check of CAPA”.
  •      The evaluation can be done as a part of the CAPA process itself, or could be integrated into other quality system elements like Quality Audits or Change Management.
  •     Recurring incidents od deviation may indicate that the CAPA was not effective od didn’t consider other potential hazards or event sequences that could cause the problem.
  •       The results of the evaluation provide information to other quality system elements as well, such as well, such as Periodic Product Quality Reviews.
  •       The evaluation results can be used to help fine-tune future CAPAs.

·         GMP references
i.     CA: C.02.011 #55
ii.   EU: EU 1, 1.4
iii. WHO: WHO Annex 3- GMP, 8.6
iv.  ICH: Q10, 3.2.4 (a)

    5.  CAPA activities are documented
  •  Records give evidence of what was done, why it was done and that it was done according to defined, approved procedures,
  • CAPA records should emphasize the rationale behind the decisions, QRM can help to provide the rationale.
  • The records of the evaluation should also be kept; they may be used as part of the Change Management program or the Periodic Product Quality Review.
·         GMP references
i.                    US: 211.192
ii.                  CA: C.02.024 #3, 3.1; C.02.024 #4, 4.1
iii.                EU: EU 1.4
iv.                 WHO: WHO Annex 3 – GMP, 8.5; WHO Annex 3- GMP, 8.6
              v.           ICH: Q10, 1.6.1

Related article in blog:
1. 7 steps of Corrective Action Preventive Action (CA-PA)

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