HANDLING, MANAGEMENT, AND INVESTIGATION OF DEVIATION

HANDLING, MANAGEMENT, AND INVESTIGATION OF DEVIATION

PURPOSE

To describe the procedure for reporting, investigating, and handling deviations that occur during any stage of processing & testing, in any quality documents, reports, or records, the handling of event that occurs during any of the activities associated with manufacturing, processing, packing operation or holding of a drug product such as but not limited to: Issuance of any incorrect materials, Out of calibration, accidental breakdown of equipment, environmental excursions or operational breakdown spillage of materials or unusual rejection of packing material during packing operation or any unexpected occurrence or unusual event which may have an impact on the identity, strength, quality, purity, and safety of a product or on the efficiency of the process.

All deviations directly or indirectly associated with manufacturing/packing / analytical / engineering operations, which can affect the safety, identity, strength, purity, and/or quality of the product which can be further as, but not limited to:-

Facility related.

Storage related.

Production related or occurred during processing.

Raw / Packaging / Intermediates / In-process stages/ FP sampling or release related.

Distribution related.

Any other.

This procedure is applicable to the handling of an event that occurs during any of the activities associated with manufacturing, processing, packing operation, testing, or holding of a drug product, quality systems which may have an impact on the identity, strength, quality, purity, efficacy, and safety of a product or on the efficiency of the process.

Deviations from approved procedures e.g. Standard operating procedures, protocol, BMR/BPR, etc., without prior authorization, shall be treated as deviation or intentional deviation.

This SOP is not applicable to Market complaints, Out of Specification (OOS) and Out of Trend (OOT) results, these shall be handled under separate respective SOPs.

It can occur in processes/work operations, facilities, equipment, quality systems, and computer systems, but not be limited to the following

Specified parameters are not met

Excessive cutting / Overwriting in the GMP records like BMR, BPRs & log cards.

A quality defect is observed.

Yield limits are not within permissible limits. Reconciliation limits are not met.

Mix-ups of products at any stage of the production process.

An operation/testing method described in any authorized documents (Specification / MOA / STP/ SOP/ Preventive Maintenance schedule of equipment) is not performed/documented or is performed incorrectly.

Issuance of any incorrect materials.

Spillage of materials.

Any breakdown due to Equipment failure/malfunction / Utility / Power Failure during the process or between planned preventive maintenance dates.

Calibration results are out of acceptance criteria (except QC department).

Missed the schedule of calibration/ qualification /validation,

Environment excursion.

Unusual rejection of packing material during packing operation.

Or any others which may have an impact on the identity, strength, quality, purity, and safety of a product or on the efficiency of the process.

ATTACHMENTS

• Deviation Form
• Deviation register
• Deviation TCD extension form
• Deviation Trend
• Flow chart for categorization of deviation

DEFINITIONS

Deviation: Any Non-Conformance, any departure, from written approved procedures or from laid down quality system (The failure of utility, material, equipment, or any system) in the organization is called deviation.

Examples of deviations include, but are not limited to, the following:

Unapproved steps added to the process.

Steps omitted from the process.

Operating steps not correctly followed/executed.

Unapproved changes to the process parameter

Incorrect issuance of raw materials

Activity performed without proper training.

Minor Deviation:

Any deviation which has no significant impact on product quality attribute, a critical process parameter, or an equipment or instrument critical process control; would be categorized as a minor deviation. Possible examples of minor deviations are given below:

• Skip of FEFO principle (first expired-first out) in raw material handling.
• Balance out of tolerance used to determine gross weight of raw materials during receipt of material.
• Pressure differential out of established limits in the class-D washing area.

Major Deviation:

Any deviation which likely has a significant impact on product quality attribute, a critical process parameter, or an equipment or instrument for critical process control which may have an indirect impact on patient safety, customer satisfaction, and product quality, safety, and efficacy is termed as a major deviation. Possible examples of major deviations are given below:

Use of unapproved reference standards to test an API or drug product.

Inadequately trained personnel to perform sterility tests.

Production started without line clearance.

Filter integrity test has been carried out using the equipment with no documented installation qualification completed.

Gross misbehavior of staff in a critical aseptic process.

Pressure differential out of established limits in aseptic fill areas.

The operational parameter is out of range for a parameter defined as non-critical.

Untrained personnel is responsible for segregating the approved and rejected raw materials in the warehouse.

Critical Deviation:

Critical deviations are the critical quality observations and/or events that may have an actual or potentially adverse effect on the identity, purity, quality, safety, or efficacy of the drug substance /drug product. It includes potential adverse effects on the stability and registration of the product. OR  Any deviation which directly has a significant impact on product quality attribute, a critical process parameter, or an equipment or instrument related to critical process control may pose a direct impact on patient safety or customer satisfaction, product quality, safety, and efficacy. Possible examples of critical deviations are given below:

Expired or rejected API component used.

Sterilization record of product-contact material used in the aseptic filling process not available or unacceptable.

Incomplete inactivation stage of fermentation.

The temperature is out of control limit during detoxification.

Non-Critical Deviation:

Non Critical deviation is a deviation from GMP or procedure that may not have any impact on product quality, purity, identity, safety or efficacy.

Corrective Action and Preventive Action (CAPA):

A concept with current Good Manufacturing Practice (cGMP) that focuses on the systematic investigation of root causes of unexpected incidence to prevent their recurrence (corrective action) or to prevent their occurrence (preventive action)

Corrective Action: action taken to eliminate the causes of an existing nonconformity, defect, or other undesirable situation, in order to prevent a recurrence.

Preventive action: Action taken to eliminate the cause of a potential nonconformity, defect, or other undesirable situation, in order to prevent occurrence.

Event or incident: Any unforeseen happening or unexpected occurrence.

Risk assessment: A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.

cGxP: cGxP is a general term that stands for current Good “x” Practice (x = Clinical, Engineering, Laboratory, Manufacturing, Documentation, Pharmaceutical, etc.). The titles of these Good “x” Practice guidelines usually begin with “Good” and end in “Practice”. cGxP represents the abbreviations of these titles where “x” a common symbol for a variable, represents the specific descriptor.

Investigation: A documented logical and/or scientific review of data related to all quality events that lead to the identification of the root cause and corrective and preventive action.

Nonconforming Material: Material that does not meet specified acceptance criteria.

Root Cause: The underlying (fundamental) reason for a detected quality issue/failure (non-conformity, defect, or other undesirable situation), which, if eliminated or corrected, will prevent the recurrence of the problem for the same reason.

Incident/ Deviation: An uncontrolled/unexpected GMP incident or deviation or an event in the form of departure from the designed systems or procedures at any stage of material receipt, manufacturing, packaging, testing, holding, and storage of drug substance and it is Intermediate/Components due to system failure or equipment breakdown or human interventions and observed at a later time during execution, audit, etc.

Temporary Change: A temporary or interim need to deviate from a currently approved requirement or to supplement, clarify or correct existing approved requirements. The term “temporary change / planned deviation” is frequently used to describe a decision to carry out a process in a different way from which it is established in an SOP, Method, or Manufacturing Batch Record (e.g. a reprocess) due to an unforeseen event. Temporary change or planned deviation needs to be fully documented and justified. Usually, these are associated with one-time events or ‘Temporary Changes’ and the change control system must be used for permanent changes.

Task: Any activity identified as a part of executing a ‘Temporary Change’ or ‘Planned Deviation’. Tasks can be of two types, i.e., pre-requisite (to be completed before execution of the temporary change or planned deviation) and non-pre-requisite (can be completed concurrently with the execution of the temporary change or planned deviation) OR it can also define as “A task list is often referred to as a checklist. This list shows the steps you need to take toward the completion of a project/action plan/investigation. It can be filled with details such as specific tasks, who’s assigned to the task, and when it needs to be done.”

Elimination – Errors: Eliminate the possibility of error. This can be accomplished by eliminating the task. For example, eliminate mixing errors by purchasing pre-mixed materials. Eliminate recording errors by directly linking the measurement device to a printer.

Event: Any unforeseen happening or unexpected occurrence.

SAFETY/PRECAUTION/EHS

Assuring timely implementation of corrective actions and ensuring
corrective actions are effective.

Ensuring all deviations/incidents in the laboratory are reported to the QA/Lab-QA on the day of discovery, but not later than the end of the next working day.

A Temporary Change or a Planned deviation may be used for, but not limited to the following; Quality / Compliance improvements, Yield improvements, Safety reasons, Batch Size changes, and Equipment/Facility- related issues.

Examples include, but are not limited to changes in equipment, location/area, processing step, control limits, packaging materials, Standard Test Procedures (STPs), and sampling procedures.

Temporary Change / Planned deviation are not to be used as a means to deviate from an approved requirement on a repetitive basis over time. Follow-up actions shall be taken to ensure that the use of this process is minimized and appropriate. A Temporary Change or a Planned Deviation is associated with one-time events and Change Control to Permanent Changes.

REPORTING OF DEVIATION

All deviations must be reported immediately to the responsible supervisor or department head on the day of discovery, but not later than the end of the next working day, and shall be logged within the same day or the end of the next working day but not later than.

Deviation shall be initiated in the following circumstances but not limited to

Processing deviation that has affected or potentially could affect a product.

A general system breakdown or failure to follow procedure.

An action limit is exceeded.

A value is outside the processing parameters.

At the discretion of the QA department, when there are excessive minor errors and/or recording errors. Errors that are found and corrected by manufacturing; however, are repetitive.

When BMRs are reviewed for product release, QA may issue a deviation report based on the information (or lack of required information) recorded in the BMRs/ Records.

A single deviation report may be used for more than one lot/batch if the deviation was repeated and the cause for the deviations is mutually related.

After initiating a deviation, the initiator can cancel the deviation if required. The cancellation shall be supported by justification and submitted to QA prior to the closure of deviation.

Any person (Initiator) can identify an incident or deviation and shall initiate an incident or deviation record. It shall be reported to the supervisor immediately and documented in the system on the day of discovery, but not later than the end of the next working day; a unique identification number shall be assigned to the record. Quality Assurance shall be informed within one (1) working day of discovery of the incident or deviation.

The concerned department person shall immediately initiate the issuance of deviation report from QA through “Documents/format requisition”.

QA person shall issue a deviation report and allocate the deviation number serially Record of deviation shall be maintained by QA.

If the deviation is related to environmental conditions, the concerned dept. shall notify the same as per the respective SOP for immediate action. Simultaneously, the concerned department shall also fill deviation reports.

For activity related to the calibration of the QC instrument, if the instrument goes out of calibration, the QC department shall fill in the deviation and carry out the investigation as per the respective SOP.

The Initiator shall provide the following information, but not limited to, as applicable:

The initiator shall fill detail required in Part-I: Initiation of Deviation (Deviation Report) with the identifier/initiator name & sign/date.

Part-I: Initiation of Deviation filled by concerned HOD of designee along with task list, immediate action, and description of immediate action based on initial assessment and reviewed by QA.

Part-I of the deviation report shall be completed on the day of discovery, but not later than the end of the next working day, and shall be logged within the same day or end of the next working day but not later.

Consent Review and Assessment of Deviation (PART-II)

The deviation form shall fill and reviewed by QA whereas shall fill by impacting department. Initiating department personnel shall fill out reviews and recommendations along with the target date of completion.

Part-II deviation form shall fill by QA based on review and approval required by External Agency/MAH QP/Customer and comment (if any) with the name of the person with sign/date of approval.

QA shall evaluate the history of deviation regarding the first occurrence or recurrence of such or a similar kind of deviation.

Based on the history, the QA shall categorize the deviation as Critical/Major/Minor and provide the rationale for the re-categorization of deviation. Category of deviation may be subjected to change due to (but not limited to) consecutive failure, recurrence, or based on potential impact, risk on system/activity/process/formula.

If the deviation is repeated, QA shall specify the deviation number and its status.

Part-II deviation form shall fill by the head QA/designee, in case of the absence of the head QA or Quality head, the designee shall categories the deviation by tick mark (ü) on Critical/Major/Minor followed by Approval of deviation as approved or rejected. In case of rejection of deviation form, justification and recommendation of deviation are required.

Head QA/designee shall evaluate the Part-II deviation form and based on evaluation, a tick mark (ü) in the given box for investigation required or not followed by a tick mark (ü) on the given box (Yes or No) for impact assessment and risk assessment.

Quality Risk Management (QRM) is required for critical and major deviations which directly impact or risk associated with the quality, safety, efficacy, and purity of drug product/facility/GxP activity.

Head QA/designee shall evaluate the Part-II deviation form and comments/additional recommendations (if any) followed by giving a target date of completion.

Root Cause, Action Plan Review (PART-III)

Deviation form Part-III, shall fill by concerned HOD/designee with action to be addressed through reference CAPA number (if applicable).

Deviation form Part-III, shall fill by concerned HOD/designee with description of action, responsible person to complete the action, closing date of action taken, status of action (weather open / closed) and attachment for evidence of action taken and completion.

After completion of action taken and the evidence/proof of action taken shall attached and fill in deviation form by concerned HOD/designee followed by QA reviewed. If action plan required not closed with in define time line then TCD (Target completion date) shall be taken to QA for completion of action/activity by filled the “Deviation TCD Extension form”.

Root Cause, shall identified as per SOP on Investigations or Root cause shall include the detail of investigation, tools used for investigation and finding and conclusion of investigation reflecting the main cause of event/deviation.

Concerned department shall follow SOP on Corrective action and Preventive Action (CAPA) to address the preventive action to avoid recurrence of same or similar failure or deviation.

Mention reference CAPA number, description of action, responsibility, status, any attachment including closing date/target date of completion (TCD).

Investigation and action plan shall be reviewed by QA and approved by head QA/designee.

Monitoring, Follow up and Closure: Part-IV

The time line for closure of deviation shall be 30 working days with CAPA. In case of investigation or CAPA is not completed within the stipulated time, an extension for timelines can be requested with proper justification i.e. action plan to complete the job, target date of completion, responsible person. Maximum 02 extensions shall be allowed, extension to be requested and justified by concern head of department and approved by QA Head/ Quality Head or by senior management, if applicable.

Proposed target date of completion for extension shall not be more than 90 working days.

If any action requires more than 90 working days then deviation shall be closed mentioning the CAPA reference number and activity to be addressed or monitored with respective CAPA.

Ensure to report the deviation reference in respective batch document or activity documents, if applicable.

Ensure completeness of deviation form with attachments as list of documents.

After completion of verification of all documents and action taken, conclude whether deviation to be closed satisfactorily.

Concerned person along with QA shall verify the completion of proposed action as defined in action plan.

Closure of deviation shall be done by QA Head/designee.

Deviation report shall be archived by QA personnel and detail of closure shall be recorded.

In case of extension of deviation PART-IV monitoring, follow up and closure shall not closed with in define time line i.e 30 working days, extension of deviation shall filled by user department or concern responsible person. User or concern department person shall justify the reason of extension and proposed extended TCD for further date of closure of deviation form.

Extension Approval status (Yes/No) shall give by Head QA/designee based on justification of extension by user department or concern person/HODs.

Only two (02) extension of deviation allowed and deviation can extended upto maximum 90 working days, if deviation not closed within 90 working days and remain in open state, than close the deviation with CAPA number and same CAPA number as reference shall give to new deviation form raise for same event/subject or further extension of time line beyond 90 working days.

Trending:

Deviation trend shall be prepared by QA

While define the criteria for trending of deviation data, the below mentioned approach to be followed:-

Open verses close deviation

Recurrence of deviation

Category wise review of deviation-Minor / Major / Critical

Root cause/source wise review of deviation

Due to malfunctioning of equipment / instrument.

• Due to human error e.g. fails to follow procedure, negligence, lack of knowledge,    lack of qualification, lack of training lack of personnel attention etc.
• Process failure e.g. formula/procedure not clear, error in master, procedural deficiency etc.

Closure of deviation within TCD and extension.

For trending of the deviations prepare the following graphs:

Time duration v/s number of deviations, with time on X axis and number of deviations on Y axis.

Frequency of deviation trending shall be once in year + 30 days.

If more than one batch is affected, a reference photocopy of the deviation shall be attached with each remaining batch record.

Site technical team (QA Head / Quality Head, QC Head, Production Head, Engineering Head or as nominated by QA Head/ Quality Head and concerned department head) shall review the deviations and relevant CAPA in order to identify and evaluate its effectiveness to avoid recurrence of same or similar failure/case.

The Deviation Analysis shall be part of the Product Quality Review and Management Review