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Standard Operating Procedure (SOP) for identification, Investigation, approval, and trending of Deviation (s) which may occur during manufacturing, packaging, or any other operation/activity.

Deviation Control Management

1.0   Objective :

• • To lay down a procedure for identification, Investigation, approval, and trending of Deviation (s) which may occur during manufacturing, packaging or any other operation / activity.

• • This SOP defines key system requirements to ensure that there is a consistent approach to investigate Deviations.

• • Compliance with this SOP will also ensure that-

• • • Each investigation conducted properly and in a timely manner.

• • • Corrective and preventive actions are implemented.

• • • Tracking, follow-up and trending mechanisms are employed to ensure compliance with GMP.

2.0   Scope – SOP for Deviation Control :

• • This procedure is applicable to control all kinds of deviation (s) at the pharmaceuticals drug manufacturing plant.

3.0   Responsibility:

• • Originating Department shall be responsible for –

• • Initiation of the deviation

• • Take immediate action, investigate and implement CAPA

• • Assessment of the deviations and recommendations.

• • Assigning the adequate resources for investigation.

• • Review investigation and deviation trends.

• • Ensure completion of commitments.

• • The technical person of the QA department shall be responsible for –

• • To help in the investigation and recommendation of CAPA.

• • The investigation team shall be responsible for –

• • To conduct a thorough investigation

• • Head – QA shall be responsible for –

• • Evaluation of the deviation and investigation

• • Ensure the effectiveness of CAPA and review trends.

• • Measure the performance of the investigation process.

• • Review deviation tends periodically.

• • Check the performance of the deviation system periodically.

4.0   Procedure – Deviation Control System :

• • Definition :

• • A deviation is an unexpected event that occurs during the on-going operation/activity/documentation, entries at any stage of the receipt, storage, manufacturing, analysis, and distribution of Drug Products / Intermediates / Raw Materials / Packing Materials.

• • Deviation (s) are to be reported as and when they occur and to be investigated for impact assessment.

• Classification of deviations:

• • Unplanned deviation:

  • An unexpected event that results in a departure from approved procedure, document, or specification.

• • It is usually discovered after the occurrence like:

• • • Sudden changes in temperature/humidity in the manufacturing area.

• • • Yield less than the standard limit or less than normally expected limit.

• • Planned deviation:

• • A proposed departure to any approved procedure, document, or specification prior to execution like :

• • • Use of different packing /raw material code other than that specified in the Specification.

• • • Use of different machines/equipment of the same principle.

• Categorization of Deviation:

• • Deviations are categorized as follows :

• • Minor Deviations:

• • The deviations is unlikely to have a detectable impact on product quality or the GMP system. e.g.

• • • Minor errors in batch record/document not affecting the integrity of the data.

• • • Spillage of material during dispensing.

• • Major Deviations:

• • Deviations that could have a moderate to a considerable impact on the product quality or GMP system. e.g.

• • • Machine Breakdown during processing.

• • • Failure to meet environmental conditions during processing.

• • Critical Deviations:

• • A deviation that could have a significant impact on the product quality or GMP system.

• • • Cross-contamination/product mix up in a product.

• • • Failure to perform a process step during the manufacturing.

• • • Use of obsolete batch document/test methods.

• • • Filter integrity failure.

• • • Mix-ups of printed packing material of the same product with different strengths.

• • Approach Covers Following elements:

• • Identification of deviations.

• • Prompt communication of deviations to the appropriate customers.

• • Identification and responsibilities of investigators.

• • Root cause analysis.

• • Evaluation of the impact on other processes, batches and facilities.

• • Evaluation of quality and final disposition of production material.

• • Procedure for initial and subsequent investigations and timely documentation.

• • Condition for continuing the processing of batches / material under investigation including QA approval.

• • Controls to assure that the status of the production material / batches involved in an investigation is properly identified and such items are segregated (if required) as directed by Quality Assurance.

• • Record retention and storage.

• • Periodic review, tracking of actions through CAPA log & trending of deviations to ensure effectiveness of deviation system.

• Guideline for Initiation of Deviation:

  • Deviation investigation may be initiated upon review of information obtained from (but not limited to)..

• • • Regulatory Quality Audit Reports,

• • • Annual Reviews,

• • • Log Books,

• • • Batch Documents,

• • • Routine used Formats,

• • • Preventive / Breakdown Maintenance,

• • • Malfunctioning of Equipment / Instrument / Utilities,

• • • Any deviation recorded during Manufacturing / Packing / Testing or any other operation/activity.

• • • Mistakes observed during the review of submitted documents to Regulatory Authorities.

• • The following are examples of different types of deviations that may be encountered.

• Initiation of Deviation:

• • All deviations shall be documented, investigated, tracked, and trended.

• • All unplanned deviations shall be reported as when they occur by the person who observes and shall be logged within 24 hours.

• • The person who observes the deviation shall inform the immediate supervisor or concerned department head/designee.

• • QA shall issue the “Deviation Form” on the request of Observer / Officer (concerned department) by assigning ‘Deviation Number’.

• • The Deviation shall be initiated by the observer/officer of the concerned department where the deviation occurs as per Annexure – I (Deviation form).

• • A complete description of deviation shall be reported (Originating Department, Material Name / Code, Batch No. / A. R. No., etc.)

• • Originating Department shall take suitable immediate action, by selecting either ‘Stop Activity’ or ‘continue activity’ in the ‘Immediate Action’ section, according to the nature of the deviation and inform department head and QA.

• • Initial impact assessment & recommendations shall be done by the concerned department head/designee and designated QA person.

• • The deviation form shall be forwarded to Head – QA for evaluation.

• • Assessment for the potential need for a Market Alert or other Regulatory Notification shall be carried out.

• • If the process cannot be stopped, the QA and production head shall decide on continuing the process until the next stage, after checking the impact of deviation on product quality and taking immediate corrective action.

• • However Head – QA shall take the final decision on batch disposition after reviewing the deviation and other related documents.

• • Head – QA / Designee shall evaluate the deviation and categorizes into minor, major, or critical based on the evaluation of GMP impact and product quality impact.

• • In general, Head – QA / Designee may recommend the investigation by the originating department and QA for the minor category of deviations and to a cross-functional team for major and critical.

• • However, Head-QA / Designee may assign the investigation responsibilities based on the nature and complexity of the deviation to the originating department or cross-functional team.

• • During the evaluation, Head – QA / Designee shall verify whether the deviation is a repeat occurrence (Review data of last one year) or not.

• • If it is a repeat occurrence, (more than 3 times) impact assessment shall be extended to verify the effectiveness of previous CAPA taken.

• • The following risk matrix shall be used for the categorization of the deviation.

• • No / minor GMP impact and no / minor Quality impact- Minor.

• • Significant GMP impact and no / minor Quality impact – Major.

• • GMP impact and significant Quality impact – Critical.

• • Significant Quality impact and no / minor GMP impact – Critical.

• • Product Impact:

• • The initial assessment may conclude either in the absence of risk or in a possible risk to product quality.

• • Any Deviation from a registered validated process and facilities as detailed within the marketing authorization and the batch record must be considered as having a potential impact.

• • In the latter case, further investigation is necessary to obtain assurance that the product quality is not compromised.

• • GMP Impact:

• • The assessment may conclude either Deviation or Investigation has an impact on regulatory compliance or not.

• • Any deviation from binding GMP standards or from inspections, commitments must be considered as having a GMP impact.

• The investigation, Recommendations, and Approval:

• • After evaluation of deviation by Head – QA, if the deviation is categorized as critical/major,

• • A cross-Functional Team comprising of technical experts from different departments (as per the nature of deviation) shall be formed to investigate the root cause of deviation.

• • QA must be a part of the investigation team.

• • The site management shall assign the resources needed for the investigation.

• • If the deviation is minor, the investigation shall be carried out jointly by a QA person along with a person from the department where the deviation happened.

• • Investigation for root cause identification shall be carried out by the investigation team using investigational methodologies described in SOP “Handling of CAPA”.

• • After root cause identification, impact assessment on the quality of product/risk assessment following SOP for  “Quality Risk Management” shall be carried out by the originating department head and QA.

• • Corrective actions and preventive actions shall be recommended to prevent the reoccurrence of the same.

• • The impact shall be evaluated on the other batches manufactured in the same campaign/equipment/area or using the same raw material/packing materials depending upon the investigation findings.

• • Head QA shall review the investigation finding and impact & suitability of proposed corrective and preventive actions and approve / reject the investigation based on the appropriateness of the root cause and actions recommended.

• • If re-investigation is recommended, Head QA shall provide the directions for re-investigation.

• • The Head – QA shall inform the deviation having impact on product quality to DRA /QP/ PL / MA (if applicable) for assessment of the impact on the product quality.

• • QA shall be responsible for review of deviations periodically and shall report the same to Head QA / Senior Management depending on the requirement.

• • QA shall forward the Investigation report to other concern department, if required.

• • After getting comments from other concern department the Deviation and Investigation report shall be forwarded to Head – QA for review and comments.

• • Determine target due date for completion and responsible person assignment for implementing corrective / preventive action(s).

• • Concerned department head and Head-QA shall be responsible for compliance of the corrective action plan.

• • After evaluation, final decision on the deviation shall be taken by Head – QA or his designee for approval of implementation of corrective and preventive actions.

• • If any impact observed on the batches distributed / exported then such cases shall be handled through the SOP for  “Recall of Products from Market”.

• • The Quality Assurance shall approve the documented rationale for continued use production materials / equipment / areas / processes / procedures impacted by the investigation.

• • The investigation report shall be approved / closed by QA, if all pertinent information for investigation trending is entered into the investigation database and CAPA that were required to be completed prior to investigation closure have been completed.

• • The deviation including investigation report (where applicable) shall be closed within 30 working days of the initiation date.

• • The initiation date is the date of observation of deviation.

• • Long term actions generated from critical and major deviation shall be logged into CAPA log for tracking and monitoring purpose in following manner:

• • • Assign CAPA number for the actions from deviation as per SOP for “Handling of CAPA”

• • • Deviation shall be closed only when all relevant actions are completed and CAPA logged for further tracking of the actions.

• Recommendation for Disposition:

• • The investigation team shall determine the fate of the item / batch etc. (e.g. reject / rework / release / quarantine) and shall recommend the disposition of the production material / equipment / area / process / procedures.

• • Recommendation shall be documented with rationale.

• • Final disposition decision related to production materials / equipment / area / Processes / Procedure shall be documented and justified by Quality Assurance.

• • Disposition actions (e.g. reject, release and return to service) shall be taken when relevant investigations are completed and closed.

• Final Review and close out of deviation:

• • The immediate action and final immediate action (if any) shall be implemented by the originating department after approval of the deviation.

• • The Head Quality Assurance shall coordinate and evaluate the implementation of immediate action and additional immediate action (if any) and decide for the close out of the deviation.

• • For critical & major deviation close out period shall be 30 days from logging the deviation and for minor deviations, the close out period shall be 15 days.

• • Any close out exceeding this period shall be recorded as extended in the remarks section in the deviation log and shall undergo a review process as per Annexure – IV

• • For deviations where root cause /investigation is not completed within the period specified, justification for not closing out, the status shall be mentioned as 1st review.

• • Incase the deviation exceeds 30 days of 1st review ,the further status and action shall be mentioned in the  2nd  review giving justification for not closing out.

• • Further if investigation is not completed within 30 days of 2nd review ,then the status and further action shall be mentioned in 3rd review giving justification for not closing out .

• • Further if investigation is not completed within 30 days of 3rd review then it shall be reported to Head QA for further advice.

• • If the deviation is closed out at 1st review or 2nd review and does not require any further actions, then the further review can be mentioned as not applicable.

• Trending:

• • Collection / compilation of data for any parameter or activity and setting of data in a specified manner to analyze the responses offered is called Trend Analysis.

• • Continuous trending shall be carried out on monthly basis as per ‘Annexure – III’.

• • Trending shall be done on broad root cause category basis (Annexure – III).

• • However investigation for repeat occurrence to be done only when it is related to a specific cause for same / similar equipment / process / product / Material etc.

• • Investigation shall be done as per Annexure –V “Investigation of Deviation Trends.

• • QA shall carry out trend analysis for all the whole year at the beginning of the next year by using monthly trend data.

• • A copy of trend analysis shall be forwarded to Head QA.

• • Head QA shall present deviation trends to management as per Performance Metrics in Quality Review Management Meeting.

• Retention of Deviation Record:

• • A copy of Deviation and Investigation report shall be kept with related batch records and / or applicable reports.

• • The record retention for all closed Deviation and Investigation reports shall be not less than 5 years or as otherwise agreed with concerned regulatory body.

• Filing of Deviation :

• • All Deviation and Investigation reports shall be kept in custody of QA and QA shall maintain the ‘Deviation Log’ as per Annexure-II.

• • Deviations for discrepancy observed during document review or system review shall also be filled and assess for its impact.

• • Refer flow chart for better understanding.

5.0   Reference (S)

• • WHO Guidelines TRS 908 Annexure 4

• • Volume 4  :   EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Chapter 1 Pharmaceutical Quality System

• • PIC/S “Guide to Good Manufacturing Practice for Medicinal Products Part I 

6.0   Glossary :

7.0   Annexure :

Annexure-I : Deviation Form

Annexure-II : Deviation Log

Annexure-III : Trend of deviation

Annexure-IV : Extended Review Deviation

Annexure-V : Investigation of deviation trends

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