PRESENTATIONS

1. CORRECTIVE AND PREVENTIVE ACTION - CAPA

2. TEAM WORK - Lessons from Geese

3. QUALITY RISK MANAGEMENT - FMEA

4. CROSS CONTAMINATION & CLEAN ROOM PRACTICES

5. STABILITY

6. CHROMATOGRAPHY - System Suitability

7. CHROMATOGRAPHY - Column Chemistry

8. GOOD DOCUMENTATION PRACTICES

INTERVIEW QUESTIONS

1. HR (HUMAN RESOURCE) INTERVIEW QUESTIONS 

2. QUALITY CONTROL INTERVIEW QUESTIONS ON WET CHEMICAL ANALYSIS

3. QUALITY CONTROL INTERVIEW QUESTIONS ON WET INSTRUMENTAL ANALYSIS

4. QUALITY CONTROL INTERVIEW QUESTIONS ON CHROMATOGRAPHY

5. INTERVIEW QUESTIONS ON SYSTEM SUITABILITY PARAMETERS - HPLC & GC

6. INTERVIEW QUESTIONS ON TROUBLESHOOTING - HPLC & GC

CHANGE MANAGEMENT SYSTEM

In any organization change in the system, process and procedures is natural as part of continuous improvements.

A formal change management (change control) system should be established as an integral part of a Quality Management System (QMS) of the organization to ensure that all the changes are appropriately identified, planned, documented, evaluated, approved & regulated.

There should be written procedures in place for technical & scientific evaluation and potential impact of the proposed changes on the quality of the medicinal products and other possibly affected systems. 

Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units, and by the quality unit(s).

Assign personnel responsible for initiation, review and approval of the specific steps of the change. It needs to be noted that a change proposal may be expanded, modified or rejected, based on the evaluation performed during the approval process.

There should be traceable system for change log like identification code or number can be assigned.

Following steps could be considered during the process of change control.

1. Change Proposal / Change Initiation
2. Change review
3. Change classification & Approval
4. Change Implementation plan & Implementation
5. Review the implemented change
6. Effectiveness verification & Closure

1. Change Proposal / Change Initiation:

• The respective personnel from the department initiate the change proposal by detailing proposed procedure/ process/ system against to the current procedure/ process/ system.
• Following should be part of change proposal

¾       Change related to  (documents/ Facility/ process/ equipment/ software/ product…etc)

¾       Current system

¾       Proposed system

¾       Reason for the proposed change

¾       Risk of the proposed change

¾       Impacted documents/ systems/ process...etc

• There should be proper reason or justification with documented evidence for the proposed change
• The risk of the each proposed change to be evaluated in a systematic way. The risk of changes like new facility establishment, new product introduction, process equipment modification/ replacement, change in manufacturing process, change in the API source, lab application software up gradation…etc shall be assessed in a formalized manner by using risk assessment techniques like FMEA.
• Few companies has a practice of change classification (Minor/ Major/ Critical) at this stage by change initiator, but as per me it should be at change approval stage by QA as defined in the respective section.
• Few companies has a practice of providing anticipated date of change implementation at this stage but as per me it should be after change approval as defined in respective section.

2. Change review:

• The proposed change shall be reviewed by all concerned personnel for adequacy.
• Starting from change initiator department head followed by related cross-functional department representatives and finally QA shall review the proposed change as part evaluation.
• QA holds the responsibility to identify the Cross-functional department representatives (i.e functional subject matter experts) that are required to evaluate the proposed change based on the type of proposed change.
• It is better to have provision in your change control SOP that states common proposed changes and required cross-functional departments as part of review process
• Finally QA designee hold specific responsibility to evaluate and assess the proposed change to identify all impacted systems/ processes /procedures w.r.t following but not limited to

¾    SOP’s

¾    Specifications/ STP

¾    MFR (Master formulae record), BMR (Batch manufacturing record), BPR (Batch packing records)

¾    Site master file & Validation master plan

¾    Qualification /Validation

¾    Drawing/ Layouts

¾    Stability studies

¾    Approved vendors/ testing laboratories

¾    Trainings

• As a part of the evaluation process, the need to obtain approval from or to notify the change to authorities and/or customers, must be evaluated.
• The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the medicinal products produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.
• Current dosage form manufacturers should be notified of changes from established production and process control procedures that can impact the quality of the API.

 3. Change classification & Approval

• Finally QA head evaluate change proposal and classify the change and approve the same.
• Changes can be classified (e.g. as minor/ major/ critical) depending on the nature and extent of the changes, and the effects of these changes may impart on the process. A classification procedure may help in determining the extent of document review, testing, validation and documentation needed in line with the proposed change.
• The classification should be based on sound justification based on the risk to product quality.

Minor : Do not have any impact on product quality attributes

Major : Likely to have indirect minor impact on product quality attributes

Critical: Have significant impact on product quality attributes.

4. Change Implementation plan & Implementation

• After the approval of change control by QA Head, the change implementation plan shall be made.
• The change implementation plan should contain following as a minimum criteria.

¾    Number changes to be done

¾    Responsible persons for each change

¾    Anticipated completion date for each change

• As per the change implementation plan, all the proposed changes shall be done with the anticipated dates if not extension to the anticipated dates can be taken with proper justification.
• When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.
• After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.
• After completion implementation of all changes, the change initiator notifies QA for further verification and closure.

 5. Review of the implemented change

• QA verifies each implementation against proposal.
• If found satisfactory, assess the requirement for effectiveness verification after certain period of time (after one month, two months, three months. Etc).
• If effectiveness verification not required, change control shall be closed.
• If effectiveness verification is required the verification plan shall be made.

  6.   Effectiveness verification & Closure

• As per the effectiveness verification plan, QA designee verifies the effectiveness of implemented changes and if found satisfactory and close the change control.

8D – PROBLEM SOLVING APPROACH

8D stands for 8 disciplines or 8 critical steps for solving problems.

The Eight Disciplines of Problem Solving (8D) is highly disciplined and effective scientific approach of problem solving typically used by manufacturing industries to find the root cause of a problem that is for resolving chronic and recurring problems.

Ford Motor Company developed this problem solving methodology, then known as Team Oriented Problem Solving (TOPS), in the 1980s. The early usage of 8D proved so effective that it was adopted by Ford as the primary method of documenting problem solving efforts, and the company continues to use 8D today.

The 8D problem solving model establishes a permanent corrective action based on statistical analysis of the problem and focuses on the origin of the problem by determining its root causes. Although it originally comprised eight stages, or disciplines, the eight disciplines system was later augmented by an initial planning stage.



8D is a systematic & scientific approach and it takes several weeks to several months in order to solve a problem and should not be used for following.

Non-recurring problems or problems which can be solved quickly by individual effort.
Problems with known root causes.
Making a decision between different alternatives.
Problems where the simplest and most obvious solution is likely to be the best or adequate solution

D0: Plan

Plan phase is a preparation step before starting the 8D process. Plan for solving problem and determine the prerequisites.

Simply it is an information collection step on symptoms of the problem

A deeper understanding of the problem and its history are necessary to determine if the 8D is the right method to be used for solving the identified problem.

D1: Define Team

Team formation is the first discipline of 8D approach.

Establish a small group of people from cross-functional disciplines with the process and product knowledge and have time to solve problem and implement corrective actions.

There should be at least one member knowing the 8D approach as subject matter expert and to keep a track of the investigation and document the minutes of meeting.

Generally 8D team consists of 4 to 8 people who are closely related to the problem. It usually involves people from different functions/departments in the organization coming together to solve a common problem.

D2: Describe the problem

The success of the root cause analysis depends on the problem description.

A correctly defined problem is 50% solved.

Define and describe the problem in measurable terms, asking questions similar to following will help you to address actual problem and not just symptom.

Key questions:

What is wrong with what?

What is happening?

What are symptoms?

Tools like ‘is’ and ‘is not’ could be used to ask questions and describe the problem

 

The problem statement will

§ Communicate the scope of the problem that the team is working on and get the team focused.

§ Provide information relevant to the problem: data and information on what the problem is and what the problem isn’t.

§ Clarify the role the team should play (determine root causes and implement or recommend a solution), specify the deadline and include monetary limits for the team.

§ Lays down expectations from the team and deliverables that will be measured.

§ Be the output of a process used to amplify the problem statement in terms of Who, What, Why, Where, When, and How Big (how much, how many, how often - level of pain) as stated above.

Gather and Verify Data

When the problem is identified, it is time to begin data collection.

The factual information and data necessary to assure a thorough cause analysis needs to be collected.

Data may have to be collected several times during this process, but the preliminary collection phase occurs now and will guide the analysis process.

Initial data gathering starts at the scene. Data has a shelf life, the longer you wait the more difficult it becomes to obtain good information.

When possible, go to the scene and take note of who was present, what is in place, when the event occurred and where the event happened. If the event is in the form of an audit finding, try to recover as much of the scene as possible.

Types of data to collect:

 Location -the site, building, department, or field location where the event took place

 Names of Personnel -operations personnel, visitors, contractors

 Date and Time

 Specifications -what are the requirements?

 Operational Conditions -start up, shutdown, normal operations

 Environmental Conditions -noise levels, visual distractions, lighting, temperature, etc.

 Communications -verbal or written, what orders were being followed?

 Sequence of Events -in what order did things take place?

 Equipment -what was being operated?

 Physical Evidence -damaged equipment or parts, medical reports

 Recent Changes -in personnel, equipment or procedures

 Training -classroom, on-the-job, none

 Other Events -have there been similar occurrences?

Once gathered, verify the accuracy of the data. Because analysis is performed based on fact. Remember, if you don’t look, you will not find the problem.

Make sure that gathered data is correct and complete. Then go where the data takes you. Do not take the data where you want it to go.

D3: Develop Interim containment action

These are the actions taken immediately after you become aware of the event to stop the event from occurring and preventing or minimizing any impact from the event. Please note that there are no actions here to correct the problem, they are just damage control

Not a problem solving but a means to control the bleeding also referred as corrections.

Define and implement those intermediate actions that will protect from problem until permanent corrective actions are implemented.

Each of these steps should be described in detail. Advise exactly what steps you took to stop the event from occurring, what was the impact and how you determined this.

Describe in detail the steps you took to contain any effects (while we are critically concerned with hardware, effects may go beyond product). If product has, or may have, been shipped to a customer, advise who and how you notified customers.

D4: Determine the Root causes & Corrective actions

Root cause analysis is about finding the true cause(s) of event.

Identify all the potential causes which could explain why the problem occurred.

Investigation process should be structured, but done in so simple manner. It should consists of following steps

· Evaluate all currently available relevant information

· Evaluate any additional information available from horizontal analysis.

· Inspect facilities or environment of the event

· Interview appropriate people

· Communicate with appropriate stake holders

· Clearly define next steps

· Decide a team if needed, Determine team makeup & Leadership

· Do not discount any data or information

During investigation organisation must make all decisions by using a risk based approach. It must determine probability of negative event and its consequences.

There are number investigation tools available but most commonly used are as follows.

1. Genchi & Genbutsu

2. Brain storming

3. WHY-WHY Analysis

4. Fish bone / Ishikawa cause & effect diagram

5. Kepner Tregoe decision making analysis

After identifying the root causes, plan for corrective actions. Corrective action is an action to eliminate the cause of detected non-conformity to eliminate the re-occurrence.

During the implementation of CAPA following shall be ensured.

· The identified CAPA addresses the root cause

· The solution can be implemented

· There is a clear understanding of overall impact of CAPA

D5: Develop the permanent Corrective actions

Plan and implement the corrective actions addressing the root causes.

The permanent corrective action is addresses identified root cause and removes / changes the conditions of the product or process that was responsible for the problem

Often the solution or solutions become obvious once the root causes are known. However, sometimes, a systematic approach is needed to use the root cause analysis to develop a solution. If the solution is obvious, select the best solution or mix of solutions that will lead to a robust, yet cost-effective, resolution. If solutions are not yet evident, follow the data trail. When solutions are not obvious, often the root cause has not been found.

Criteria for choosing the best solution (Corrective Action):

· Practical & Feasible

· Cost effective

· Robust & Error proofing

Validation of solution / Effectiveness of corrective action:

It is necessary to establish that the solution will make the problem go away without leading into other unwanted issues. That is why the 8D team should try out the solution with small quantities first to verify its effectiveness.

A design verification test (DVT) and/or a reliability demonstration test (RDT) may be required depending on the solution.

The solution is first to be tried on small lots to validate that it has indeed solved the problem prior to full implementation.

D6: Implement & validate permanent Corrective actions

Once the solution and its implementation are approved, the next step is to create an Action Plan.

The Action Plan outlines what steps are needed to implement the solution, who will do them, and when they will be completed.

A Simple Action Plan merely documents what needs to be done, who will do it, and when will it be done by.

A complex solution needs more thorough planning and documentation.

D7: Take preventive measures

The job of a problem-solving team is not complete once the solution is implemented. Preventing recurrence is an important part of a problem’s solution.

To prevent recurrence of the problem, the team must verify that the outcome of their Action Plan works and they must validate that the outcome is on-target.

Verification is testing that the solution produces the desired outcome; validation is ensuring that the outcome really solves the problem.

D8: Closure and team celebration

Once a team has completed implementing the solution and ensured that the solution works, all team members deserve to be congratulated. Team members need to know that their efforts are appreciated and that the organization knows about their accomplishments.

The organization (leadership group) shall recognize the team for their efforts in a timely manner.

ROOT CAUSE ANALYSIS - SYSTEMATIC APPROACH

ROOT CAUSE ANALYSIS – Digging deeper than symptom: 

A systematic approach to get the true root cause of the problem.
The purpose of the root cause analysis is to improve the product or processes by getting the bottom of the problem or unexpected event by
  Identify the factor that produced the problem
  Determine what behaviors, actions & conditions need to be changed; to prevent re occurrence.

CAUSE: 
A set of conditions or circumstances that
  Allows a condition to exit or event to happen, or
  Makes a condition exist or event happen

ROOT CAUSE:

The fundamental reason for an event which if corrected, would prevent re occurrence.
 A factor that caused the non-conformance. When we fix it, the problem goes away and does not come back.

We must be ever vigilant of the difference between problem symptoms and problem root causes. Examining the analogy of a weed in your lawn is helpful in seeing the difference. The weed is the symptom; it is what you see above the surface. Cutting the weed, even at ground level is rarely helpful because the root of the weed is still alive and will regrow the weed which you will see at a later date. By not digging the root of the weed out of the ground is analogous to not “getting to root cause”.

 ROOT CAUSE ANALYSIS – Philosophy & Approach: 

 Each problem is an opportunity because it can tell a story why and how it occurred.
 True problem must be understood before action taken. Root case analysis is a collective term that        describes a wide range of approaches, tools and techniques used to uncover the cause of problems.

Root cause analysis Approaches: But not limited to 
 1. Four step method (PDCA & Form, Norm, Storm, Perform)
 2. Five Step method (DMAIC)
 3. Six step method
 4. Eight step method (8D Method)
 5. Nine Step : Boeing
 6. Toyota A3
 7. Kepner Tregoe method

Root cause analysis Tools: But not limited to
1. Genchi & Genbutsu (Go & See)
2. Brain storming
3. Fish bone analysis / 6M Method / Ishikawa diagram / Cause & effect diagram
4. Why-Why analysis
5. Pareto Charts
6. Run Charts
7. Control Charts
8. Flow charts
9. Histogram
10. Scatter diagrams
11. Affinity diagrams
12. Tree Diagram

STABILITY STUDY

What is Stability?

Stability is a study to provide evidence on how the quality of product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.

i.e. evaluation of product under recommended storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture.

To establish a re-test period for the drug substance or a shelf life for the drug product at recommended storage conditions.

In simple words Stability can be also defined as

The capacity of a drug to remain within specifications established to assure its identity, strength, quality and purity”

Stability study Lifecycle:

Stability studies are incorporated at all stages of drug product life cycle from early stages of product development to last stage follow-up studies. In particular the life cycle can be divided in to 6 different stages as follows.

Stage-1: Early stage stress and accelerated testing with drug substance.

Stage-2: Accelerated & Long term testing of drug substance

Stage-3: Stress testing on scale up batches of drug products

Stage-4: Accelerated & Long term testing for registration purpose

Stage-5: On-going stability testing.

Stage-6: Follow-up stabilities.

Stress Testing:

Ø  Stress testing is to be carried out on a single batch

Ø  The testing should include the effect of temperature (50/60 ^oC, i.e. 10 ^oC increment) above that of an accelerated testing, humidity (e.g.: 75% RH or greater) where appropriate oxidation & photolysis on the product has to be performed.

Ø  Stress testing can help identify the likely degradation products which can help to establish:

         i.   The degradation pathways.

         ii. The intrinsic stability of the molecule.

         iii. Developing & validating the suitable analytical procedures.

Ø  Photo stability Testing (ICH Q1B) should be an integral part of stress testing.

Selection of batches:

Ø  Data from at least 3 primary batches required.

Ø  Primary batches could be from pilot / plant scale.

Ø  Plant / pilot batches should be Apple to Apple (process, equipment, route should be similar).

Ø  The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale.

Container Closure system:

The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

Specification:

Ø  Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, is addressed in ICH Q6A and Q6B.

Ø  specification for degradation products in a drug substance is discussed in Q3A

Ø  Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes.

Ø  Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed will depend on the results from validation studies.

Ø  The testing should cover as appropriate : chemical, physical, biological & microbiological parameters

Testing Frequency:

Long Term      :      First year      : Every 3 months.

                            Second year  : Every 6 months.

                            Thereafter     : Annually.

Intermediate   :     0, 6, 9, 12 months. (Min 4 time point)

         Accelerated     :     0, 3, 6 months. (Min 3 time point)

Ø  If results from accelerated studies are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design.

Ø  When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points (0, 6, 9, and 12) study is recommended.

Storage Condition:

A very important point in conducting stability studies are storage conditions.

World has been divided in to 4 stability zones based on real climate conditions in the respective regions 

ICH Stability zones

Zone	Type of climate	Kinetic Average temperature	Average relative Humidity
Zone I	Temperate Zone	21°C	45 %RH
Zone II	Mediterranean/ Sub tropical zone	25°C	60 %RH
Zone III	Hot dry zone	30°C	35 %RH
Zone IV	Hot / Humid (Tropical zone)	30 °C	65 %RH
Zone IVb	Hot / Very Humid	30 °C	75 %RH

Long term testing Conditions:

Climate Zone	Temperature	Humidity	Minimum Duration
Zone I	21°C±2°C	45% RH ± 5% RH	12 Months
Zone II	25°C±2°C	60% RH ± 5% RH	12 Months
Zone III	30°C±2°C	35% RH ± 5% RH	12 Months
Zone IV	30°C±2°C	65% RH ± 5% RH	12 Months
Zone IVb	30°C±2°C	75% RH ± 5% RH	12 Months
Refrigerated	5°C±3°C	No Humidity	12 Months
Freezer	-20°C±5°C	No Humidity	12 Months

Accelerated testing conditions:

Climate Zone	Temperature	Humidity	Minimum Duration
Zone I to 1Vb	40°C±2°C	75% RH ± 5% RH	6 Months
Refrigerated	25°C±2°C	60% RH ± 5% RH	6 Months
Freezer	5°C±3°C	No Humidity	6 Months

Intermediate testing conditions:

Climate Zone	Temperature	Humidity	Minimum Duration
All zones	30°C±2°C	65% RH ± 5% RH	6 Months

Storage condition	Long term	Intermediate	Accelerated
Ambient	25°C ± 2°C/ 60% RH ± 5% RH                 (or) 30°C ± 2°C/ 65% RH ± 5% RH	30°C ± 2°C/ 65% RH ± 5% RH	40°C ± 2°C/ 75% RH ± 5% RH
Below 30°C	30°C ± 2°C/ 65% RH ± 5% RH	NA	40°C ± 2°C/ 75% RH ± 5% RH
Cool (15°C-25°C)	25°C ± 2°C/ 60% RH ± 5% RH	30°C ± 2°C/ 65% RH ± 5% RH	40°C ± 2°C/ 75% RH ± 5% RH
Refrigerated	5°C ± 3°C	NA	25°C ± 2°C/ 60% RH ± 5% RH
Freezer	- 20°C ± 5°C	NA	NA

Ø  If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Ø  If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and  “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria

Ø  If “significant change” occurs between 3 & 6 months of accelerated study, data on long term study should be submitted.

Ø  If “significant change” occurs within 3 months of accelerated study, it is unnecessary to continue further testing.

Ø  In the absence of an accelerated storage condition for drug substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition, e.g., during shipping or handling.

Ø  Drug substances intended for storage below -20°C should be treated on a case-by-case basis.

Stability Commitment:

Ø  When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re-test period.

Ø  If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed re-test period.

Ø  If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue these studies through the proposed re-test period and to place additional production batches, to a total of at least three, on long term stability studies through the proposed re-test period.

Ø  If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed re-test period.

The stability protocol used for long term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified.

Statement & Labelling:

Ø  A storage statement should be based on the stability evaluation.  Wherever applicable, specific instructions should be provided. For eg: drug substances that cannot tolerate freezing.

Ø   Avoid use of “ambient condition” or “Room temperature”.

Ø   Need direct link between the label storage statement & the demonstrated stability.

Ø   A retest period for drug substance should be derived from stability information, and should be displayed on the container label as appropriate.

Testing conditions where stability has been shown	Required labeling statement	Additional labeling statement, where relevant
25 ± 20C / 60 ± 5% RH (long term) 40 ± 20C / 75 ± 5% RH (accelerated)                        or 30 ± 20C / 65 ± 5% RH (long term) 40 ± 20C / 75 ± 5% RH (accelerated)	None	Do not refrigerate or freeze.
25 ± 20C / 60 ± 5% RH (long term) 30 ± 20C / 65 ± 5% RH (intermediate) or 30 ± 20C / 65 ± 5% RH (long term)	Do not store above 30 0C or Store below 30 0C.	Do not refrigerate or freeze
25 ± 20C / 60 ± 5% RH (long term)	Do not store above 25 0C or Store below 25 0C.	Do not refrigerate or freeze.
5 ± 30C (long term)	Store in a refrigerator or Store & transport refrigerated	Do not freeze
Below zero	Store in a freezer or Store & transport frozen	None

S.No	Storage problem	Additional labeling statements* depending on the packaging
1.	Sensitivity to moisture.	Keep the container tightly closed
2.	Sensitivity to moisture.	Store in the original package.
3.	Sensitivity to light	Store in the original package.
4.	Sensitivity to light	Keep the container in the outer carton.

EVOLUTION OF STABILITY DATA TO ESTABLISH RETEST:

·      Retest date shall be established by extrapolation of real time data

·      Extrapolation is the practice of using a known data set to infer information about future data. Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition.

EVOLUTION OF STABILITY DATA TO ESTABLISH RETEST FOR DRUG SUBSTANCE INTENDED FOR ROOM TEMPERATURE STORAGE

Accelerated condition	Long term /ACC Data	Data willing to statistical analysis	Retest period / Shelf life (Y) (X= available long term data)
No significant change	Little or no variability over time	-NA-	Y = 2x   (Should NMT X+12)
	Showing variability over time	Yes	Y = 2x    (Should NMT X+12)
		No	Y = 1.5x  (Should NMT X+6)
Accelerated condition	Intermediate Data	Data willing to statistical analysis	Retest period / Shelf life
Significant change	Significant change	-NA-	Y = x
	No Significant change	Yes	Y = 1.5x   (Should NMT X+6)
		No	Y = x + 3

If no significant change at accelerated stability data for 6 months.

Long-term and accelerated data showing little or no change over time and little or no variability

	X	Y
Accelerated (6months)	Long Term (9 months OK)	y = 2x (Should not more than X+12) re-test date is 18 Months
Accelerated (6months)	Long Term (12 months OK)	y = 2x (Should not more than X+12) re-test date is 24 Months
Accelerated (6months)	Long Term (18 months OK)	y = 2x (Should not more than X+12) re-test date is 30 Months
Accelerated (6months	Long Term (24 months OK)	y = 2x (Should not more than X+12) re-test date is 36 Months
Accelerated (6months)	Long Term (36 months OK)	y =  x re-test date is 36 Months (No extrapolation beyond 36 months)

If significant change at accelerated stability data for 6 months

	X	Y
Accelerated (6months)	Intermediate 9 months OK	y = 1.5x (should not more than x+6)  re-test date is 13.5 months
Accelerated (6months)	Intermediate 12 months OK	y = 1.5x (should not more than x+6)  re-test date is 18 months
Where significant change occurs at the intermediate condition, the proposed retest period or shelf life should not exceed the period covered by long-term data.  In addition, a retest period or shelf life shorter than the period covered by long-term data could be called for.