What is SOP / Standard Operating procedure?

SOP (Standard Operating procedure) is a set of written instructions that documents a routine or repetitive activates followed by the organization. The development and use of SOPs are an integral part of a successful quality management system as it provides individuals with the information to perform a job properly and facilitates consistency in the quality and integrity of the product

Types of SOP’s (Standard Operating procedures_

Basically the SOPs are classified as three types

1. Functional SOP

Functional SOP defines the functions handled in the GMP environment (Eg. Handling of Change, Handling of Failures, and General house keeping). These kinds of SOPs are prepared based on common Industrial practices and reference to the guidelines.

2.      Technical SOP

The so called Batch manufacturing record, Standard testing procedures etc. will comes under this type this will directly deals with the product manufacturing and testing.

3.      Guidelines SOP: Guidelines SOPs will guide the personnel to handle the activity (Eg. Preparation of training module). This kind of SOPs is very limited and no need to be followed what exactly Guidelines SOP says. Pharmaceutical organization may not need to have these guidelines SOPs.

Functional and technical SOP need to be implemented and followed strictly.

Basic requirements of SOP

1. SOP should be prepared and reviewed by user department at two different levels, followed by reviewed and approved by Quality assurance department.
2. All the SOPs need to be trained, training evaluated and implemented
3. SOPs should facilitate the records (Work sheets/raw data sheets) for documentation to show the consistency in implementation and following the procedure.
4. SOP should have the distribution, reterval and archival system.
5. Organization should follow the uniform procedure/format for preparing SOP
6. Each SOP should have a unique identity (Numbering) and should have the revision status to show the number of revision happened and existing revision

Where SOPs required?

The activity that influence the quality of product directly or indirectly need to be controlled through an SOP and its records. 

Basic elements of SOP

This is the step by step guideline to define the effective SOP, here explained is common industrial practices in the pharmaceuticals.

SOP should have the following elements consistency.

1. HEADER: The company name, document type, department, pagination, title, SOP No., Supersedes, Issue date, Effective date and review date shall appear as header on every page of the document.

2. FOOTER: The ‘Prepared by’, ‘reviewed by’ and ‘Approved by’ shall appear as footer on every page of the document. Name and designation of the person preparing, reviewing and approving the SOP shall be printed

3. CONTENT OF THE SOP

a) Reason For Revision: In the first page of the SOP format (Annexure-2), mention in brief, the revision history of the current revision number and its preceding revision number. History of other previous revisions shall be referred to in the obsolete SOPs.

B) Purpose: Mention the intent of the SOP for which the SOP is being made.

C) Scope: Provide limits to the use of the described procedure, e.g. limit the use to certain equipments, departments, utilities, area.  Also the applicability of the SOP is mentioned here.

D) Responsibility: Specify the designations of the persons responsible for performing, monitoring, implementing and ensuring compliance of the described activity, if applicable.

E) Abbreviations (If Applicable): Expand the short terms used in the document. If there is no abbreviations mention “not applicable”

F) Definitions (If Applicable):  Define the terms, if any, used in the document. If there is no definitions mention “not applicable”

G) Procedure :

Describe the detailed procedure to be followed to fulfill the intent of the SOP including follow-up actions in case of failures where applicable.

Use active verbs and direct statements to describe the procedure. e.g. 'Weigh 150 kg raw material or 'add 100 L of purified water'.

Describe the procedure 'step-by-step' and in chronological order.

Effectively communicate the procedure.        

Where applicable, describe in the procedure, actions to be taken in case of failures, e.g. handling temperature excursions, handling out of calibration, etc.

H) Environmental Health And Safety (If Applicable) : If applicable, specify health, safety and environmental protection measurements / precautions required to be followed while executing the SOPs related to equipment, utility and handling of chemicals / reagents. If there is no health safety and environmental protection required mention “not applicable”

I) Document Distribution List: The distribution requirements shall be documented in the SOP. Any additional distribution shall be recorded in the document distribution record QA/F/044 and updated into the SOP during subsequent revisions.

J) References (If Applicable) : Wherever applicable, give references, cross reference to other SOPs, text books, pharmacopoeias, regulatory requirements, manuals, general information, flow diagrams, pictorial reference, photographs and any other authentic supporting references to be referred during execution of the described procedure. If there is no references mention “not applicable”

K) Enclosures (If Applicable) :

Give a list of attachments to the SOP as Annexure. This includes the flowchart approach to SOPs which facilitates training and explanation of SOP. Annexure include formats to record the data, observations, labels, checklists, etc. generated for demonstrating compliance to the SOP. If there is no enclosures mention “not applicable”

The final copy of  SOP shall be printed on a standard A4 size white (210mm x 297mm) paper using Times New Roman

Numbering Of SOPs:

The SOP No. is a unique alphanumerical code given to every SOP.  The alphabetical part in the SOP number indicates the department to which the SOP belongs.  The numerical part is a unique serial number given to the SOP and this is followed by the revision status of the SOP.  The following are the code numbers and number of characters in the SOP No., department wise.

The font sizes and style of each section eg Header, content etc. should be followed in each SOP as uniform.

Root Cause Analysis (ROA) in pharmaceuticals

Root causes analysis process is a four-step process involving :

1.      Data collection and preservation

2.      Investigation and Analysis

3.      Root cause identification

4.      Recommendation generation and implementation.

Step 1: Data Collection and Preservation

The first step in the analysis is to gather data covering men / machine / materials / methods or others as applicable. Without complete information and an understanding of the incident, the causal factors and root causes associated with the incident, cannot be identified.

-                  People involved should be interviewed.

-                  Record should be reviewed.

-                  SOP adequacy to be checked.

-                  Previous history to be referred and data collected.

Step 2: Investigation and analysis (by using FTA method)

FTA provides a way for investigators to organize and analyze in chronological way the information gathered during the investigation and to identify gaps and deficiencies in knowledge as the investigation progresses. The FTA is simply a sequence diagram that describes the events leading up to and following an incident, as well as the conditions surrounding these events. The final step in FTA involves identifying the major contributes to the incidents (i.e. causal factors).

Procedure for Root Cause Analysis  

-    Preparation of the FTA shall begin as soon as investigators start to collect information about the incident. They shall begin with a “skeleton” chart that is modified, as more relevant facts are uncovered.

-    Data collection shall continue until the investigators are satisfied with the thoroughness of the chart and hence are satisfied with the thoroughness of the investigation.

-    When the entire incident has been charted out, the investigators are in a good position to identify the major contributors to the incident. These are labeled as causal factors

After identification of all the causal factors, the investigators shall begin root cause

-       identification. Each causal factor shall be analysed, one at a time, using the questioning techniques, i.e. how, why, what, when, who & where.

Procedure for FTA

The procedure for performing a fault tree analysis consists of the following steps after defining the TOP event for analysis and data collection :

1.      Define the treetop structure. Determine the primary difficult sources (major factors like events / resource / conditions) that most directly lead to the TOP event. (LEVEL-1)

2.      Explore each branch of primary difficulty source in successive levels of detail.  Analyse the major factor in details to get possible type of difficulties under individual major factor. (LEVEL-2)

3.      Explore each branch of individual type of difficulty to find major root cause category.   Analyse each individual type of difficulty by using tools like ‘WHY WHY ANALYSIS’ to get possible major root causes category. (LEVEL-3)

4.      Explore each branch of individual “major root cause” category to find possible “near root cause”. Further, analyse each individual” major root cause” by using tools like “WHY WHY ANALYSIS” to get possible near root causes. (LEVEL-4)

5.      Solve the fault tree for the combinations of events, resource and conditions contributing to the TOP event to pinpoint the actual / near by root cause.  Examine the fault tree model to identify all the possible combinations of events, resource and conditions that can cause the TOP event of interest. A combination of events, resources and conditions sufficient and necessary to cause the TOP event is called a minimal cut set.

6.      Identify important dependent failure potentials and adjust the model appropriately.  Study the fault tree model and the list of minimal cut sets to identify potentially important dependencies among events, resource and conditions. This will help to pint point the actual root cause or close to it.  (LEVEL-5)

7.      Use of results in decision making. Use results of the analysis to identify the most significant vulnerabilities in the system and to make effective recommendations for reducing the risks associated with those vulnerabilities.

Step 3: Root Cause Identification 

   

Root cause identification, involves the use of a decision tree to identify the underlying reasons for each causal factor identified during FTA. The identification of root causes, helps the investigator of a specific incident determine the reasons why the incident occurred so that the reasons how the incident can be fixed.

            

Step 4: Recommendation Generation and implementation    

The next step is the generation of recommendations. Following identification of the root cause(s) for a particular causal factor, achievable recommendations for preventing its recurrence must be generated.

Corrective action and Preventive Action | CAPA in Pharmaceuticals

Definitions:

Corrective Action: Action taken to eliminate the causes of an existing non-conformity, defect or other undesirable situation in order to prevent recurrence.

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

Handling of Corrective and Preventive action

In Pharma working quality management systems will identify non-conformities, non-compliances arising due to various causal factors and situations as follows:

-          Customer Audits

-          Regulatory audits

-          Internal Audits

-          Out of specifications (OOS)  

-          Product quality review

-          Deviations

-          Out of calibrations (OOC)

-          Customer complaints

-          Product Recalls

Such non-conformities and non-compliances should be investigated thoroughly with an aim to identify the route cause, root cause can be done as “Root cause analysis” Click to view.  In some cases root Cause may not be identified that need to be justified properly and effort for identifying the root cause should be documented.

Based on the root cause analysis Corrective and Preventive action should be identified, defined and implemented

General Principles

1.      Pharma Manufacturer Should have an written procedure for Handling of CAPA with documentation and records

2.      All Corrective and preventive action should be time defined and tracked for closure.

CAPA with Examples:

Example: 1

Situation:  A spray nozzle on a tablet coating device developed partial plugging during the coating of a batch or product xxxyyy. This resulted in unevenly coated tablets. An electrical out age in the plant delayed processing by 12hours.

Root Cause: The root cause was determined to be the use of a suspension that washed beyond the maximum holding time after preparation

Corrective action:

Modify the xxxyyy manufacturing instructions to state more clearly the need to prepare and utilize the coating suspension within the specified holding time.

Modify the equipment cleaning and setup procedures to require full nozzle disassembly after each batch.

Prevention action:

Examine spray nozzle sand suspension make up SOPs for other products onsite.

Example 2:

Situation:  Deviations of incorrectly weighed ingredient have been reported. The error was detected during routine manufacturing checks. The incorrect weight of ingredient was dispensed in the Central Dispensary

Root cause: The immediate cause is a calibration failure of the scale used to dispense the ingredient. This was caused by reference weights being cleaned and Not re-calibrated prior to use. Root cause is the absence of any procedural controls for reference weights.

Corrective action: A procedure for the handling of reference weights was developed and implemented. All reference weights were checked to an agreed plan devise d on the basis of risk to product quality.

Preventive action: Communicate/share learning’s with other sites within the network.