Handling of Deviation

Dr. A. Amsavel

Introduction

Content

• Introduction- GMP• Definition• Deviations- Quality system requirement• Classification• Examples• Investigation• CAPA• Documentation

System for Quality

What is tested is not sold What is sold is not tested

So,Quality is not testing of product.

It should to be built in each stage of process/operation.

Principle of GMP

Quality, Safety, and Effectiveness must be designed and built into the product;

Quality cannot be tested into the product;

Product Quality depends on:Each step in a manufacturing process must be controlled to maximize the probability that the finished product will meet all its quality and design specifications.

GMP Guidance/ Reference

ICH- Q7 FDA- CFR-210 &211 Schedule – M WHO GMP : Technical Report series - 937 EU GMP guidelines, Part I annex 15 EU GMP Part II chapter 13 PIC/S Recommendations PI 006-3

Requirement

Quality system requirement• OOS• Deviation• Customer complaint• Product recall & return• Change control• Risk assesment

ICH: Q7 Contents (Chapters)

1.0. Introduction

3.0 Personnel

2.0 Quality Management

5.0 Process equipment

4.0 Building and premises

7.0 Materials Management

6.0Documentation & Records

9.0 Packaging and labelling

8.0 Production & in-process Controls

11.0 Laboratory Control

13.0 Change control

10.0 Storage & Distribution

15.0 Complaints and recalls

14.0 Rejection and re-use of materials

12.0 Validation

16.0 Contract manufacturing

Deviations

• Associated with limits vs. specifications

• GMP mistakes or errors– Reprocessing or Rework– Unapproved changes– Performing an activity without proper

training – Outside of operating parameters or in-

process control limits – Failure to follow written SOPs or approved

batch record instructions

Definition

Deviation • Departure from an approved instruction

or established standard.

• Deviation is a departure from approved procedure or established standard or specification

Deviation – GMP requirement

From ICH

• 2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.

• 2.53 Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

Deviation – GMP requirement

• 8.15 Any deviation should be documented and explained. Any critical deviation should be investigated.

• Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

• Any deviations from this should be evaluated to ensure that there are no detrimental effects upon the fitness for purpose of the material.

Deviation – GMP requirement• 5.35 Deviations from approved standards of calibration on critical

instruments should be investigated to determine if these could have had an impact on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration.

• 6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.

• 12.22 A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

Types of deviations

A deviation is an activity performed differently and/or modified than that specified in an approved document.

There are two types of deviations1) Planned Deviation.2) Unplanned Deviation.

Planned Deviation • Planned deviations, which are described, and pre-approved

deviation from the current operational document/system, covering a specified period of time or number of batches.

• Planned deviation shall be approved before execution

• Planned deviations should be handled through the QA approved change control procedures.

• All changes should be evaluated for product impact, significance

– The need for requalification or revalidation

– Changes ultimately approved or rejected by QA.

• QA should insist that planned deviations not be used; all deviations should be unintentional, unplanned, or unexpected.

Unplanned Deviation

• Unplanned deviations also called as incident.

• Incident can be defined as unplanned or uncontrolled event in the form of non-compliance from the designed systems or procedures at any stage of manufacturing, packaging, testing, holding and storage of drug product due to system

Classification

Critical/major/minor

Quality Impacting Incident:–

• Quality impacting incidents are errors or occurrences during execution of an activity which will affect the Quality, Purity, Strength of the drug product.

Quality Non-impacting Incident:-

• Quality Non-impacting incidents are errors or occurrences during execution of an activity which may have no impact on the quality, purity and strength of a drug product

Documentation

• Deviation reported in real time – Timely notification of QA (within 24 hours)

• Thorough root cause investigation• Timely investigation (within 30 days)• Corrective actions proposed and initiated or

completed• Investigation closed• Implicated batch(es) released or rejected• Preventive actions initiated and closed

Documentation

• The guidelines require that ANY deviation to the defined processing steps in the production records should be documented. It may be useful to have an additional page in the production record to allow easy recording of unexpected occurrence or deviation to the standard instructions.

• It is then the responsibility of the persons reviewing the completed production records (Production) to decide which deviations could be considered critical and require investigation.

• The Quality Unit should check the deviation records (not the full production/batch records!)

• The Quality Unit should check the deviations to see the procedure was followed and CRITICAL deviation records for impact on API quality and ensure that critical deviations were investigated (reference 2.22 and 6.72 ICH Q7).

Documentation• A critical deviation is defined as a variation to previously established

critical parameters or a significant variation to standard operations which COULD affect the quality of the API or intermediate. Critical deviations should always be investigated and corrective actions identified.

• investigation and its conclusions should be documented. Q7A allows the company to determine the extent of the investigation or explanation.

• Where deviations recur on a regular basis the need for example to re-qualify equipment, retrain operators, redefine the process parameters or to implement other appropriate actions should be considered.

Examples of deviations

Examples of deviations are: • Incorrect charging of raw materials • Temperature, pressure, vacuum parameters outside defined limits. • Operating instructions not correctly followed. • Breakdown of process equipment or failure of utilities. • Equipment out of calibration. • Production records not adequately completed. • Temporary alteration to defined production instructions • In Process Control Limits not achieved. • Alternative production equipment used at short notice. • Extraneous contamination of API and intermediates • Any other unplanned event.

Observation

• General FDA 483 Observation• Corrective actions do not ‘match’ or

support definitive or potential root causes.

Deviation investigations

• Deviation investigations must not be biased from the start– From an FDA or cGMP perspective, the purpose of

conducting a deviation investigation is not to “release the batch.”

– The true purpose of a deviation investigation is to • determine the root cause for the “deviation”\• implement appropriate and meaningful corrective

actions, and • evaluate the implicated system (e.g., the training

program) once a pattern of repeating deviations is noted.

Investigation steps

1. Discovery of the Deviation2. Documentation of the Events 3. Immediate Corrective Action4. Investigation of the Root Cause5. Causal Analysis6. Corrective Action7. Effectiveness Evaluation

Investigation

• What was discovered?• Who was involved?• When did the event occur?• Where did the deviation occur?• How was the deviation discovered?• How frequently does the process occur?

THERE IS A BIG DIFFERENCE BETWEEN WHAT HAPPENED VS. WHY OR HOW SOMETHING HAPPENED

Investigation

• Are there environmental problems?• Are the work conditions suitable?• Are there process flow problems?• Are there facilities problems?• Are there any equipment or materials problems?• Are instructions for use clear?• Are there problems with staff communication or staff training?• Is there adequate supervision? • Are there problems with the methods, SOPs, forms, or task analysis?• Do the steps performed match the operating procedures?• Has a process recently changed?

Investigation • Understanding of how or why the deviation occurred.

• Understanding of the circumstances at the time of the deviation

• Determination of other products, processes, or individuals were involved

• Gathering of data to aid in the accurate future determination of a root cause and development of corrective action.

Data Collection Interview: Staff, Customers, Suppliers Review: Policies, Procedures, Forms Record Review: verify the relevant records

Corrective and Preventive Action

• CAPA (Corrective and Preventive Action) is a deviation management program that focuses on the systematic investigation of discrepancies, adverse events, or failures.

• If used properly, the CAPA system will provide a means to prevent the deviation from recurring.

• systematic investigation of the deviation.

Corrective action:

• An action taken to eliminate the root cause and symptom of an existing deviation or nonconformity to prevent recurrence

• This is a REACTIVE action that eliminates problems identified in products, services, or processes and takes care of the immediate problem

Preventive action:

• This is an action taken to eliminate the potential causes of a nonconformity, defect, or other undesirable situation in order to prevent occurrence.

• This is a PROACTIVE action which avoids deviations through planned activities. It also eliminates or reduces the recurrence of the problem.

Immediate action

• Examples of Immediate Corrections• Products

– Quarantined– Isolated– Discarded

• Equipment– Removed from Service– Replaced

• Processes– Manufacturing Suspended– Test Results Withheld– Recovery Procedure Halted

Developing the Corrective Action

• SOPs• Process changes• Training or Retraining• Implementation of automation or new

equipment • • •Decide on the implementation timeframe• •Determine the method of CA communication• •Determine staff involved in carrying out the CA

Effectiveness Evaluation• The Corrective action was completed and implemented as planned• The corrective action was effective in the reduction or halt of

recurring deviations. • Verify that corrective action was properly implemented• Determine data source for Effectiveness Evaluation• Determine when to perform Effectiveness Evaluation• Determine evaluation period• Consider impact of learning curve• Determine success criteriaDepending on the organizational SOP, the

evaluation for • effectiveness should begin within 60 days of the • corrective action plan implementation date.

Importance of documentation

• If it isn’t documented, it didn’t happen• If it isn’t documented, it doesn’t exist.• Precise, economical word usage