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Online pharmaceutical quality assurance and validation procedures and manuals
Online pharmaceutical quality assurance and validation procedures and manuals


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Guideline for the Validation of Excel Spreadsheets:

1 Purpose

The purpose of this document is to provide guidelines for a suitable approach for the qualification of Excel spreadsheets used in direct, or in-direct, GxP related activities at all GMP facilities.

2 Scope

The procedure applies to the initial qualification and re-qualification of Excel spreadsheets, designed and used for making quality based decisions in GxP environments at the GMP facility. These areas include but are not limited to:

Quality Operations
Manufacturing Operations
Regulatory Affairs

The scope does not include those spreadsheets which are single use only (prepared for a specific, one off tasks) or those which are used for organization of personal, or departmental work plans. These should be verified at each time of use as appropriate.

3 References

Good Automated manufacturing Practice Guide (GAMP), Version 4, ISPE
David Harrison and David A Howard, A Pragmatic Approach to the Validation of Excel Spreadsheets, Pharma IT Journal, Vol1 No.4 October 2007

4 Introduction

Spreadsheets can be used to record and manipulate (change, delete, add) GxP data and as such need to be managed to ensure the continued integrity and security of that data. While some are no more than fancy calculators others are embedded with special features and use intricate logic in the form of Macros that are in effect computer programs.

Spreadsheets can be classified into GAMP categories depending on use and contents of the spreadsheet. This will impact the level of validation effort that is applicable just as with other computerized systems. Spreadsheets which fall into GAMP Category 3 guidelines (Table 1) do not require full validation activities but should be held under appropriate security conditions.
Below is the GAMP Categories for Spreadsheets

GAMP Category



   used solely to produce paper documents


   more complex such as those that incorporate templates


   uses macros, lookup tables &/or sophisticated logic

Spreadsheets which have calculations that are fully explained on the spreadsheet and which undergo verification with each use do not need to be fully validated, however where there are templates for the spreadsheets appropriate security conditions, including password protection should be provided.

This guidance outlines steps that shall be followed to request, approve, develop, test, implement, maintain and support a controlled spreadsheet application.

5 Validation of a Spreadsheet Application

5.1 Functional Requirements Development

Spreadsheet applications may be developed by individuals (e.g., laboratory analysts) who have been qualified by training or experience as a Spreadsheet Application Developer.

The Functional Requirements Document incorporating user requirements and functional specifications shall be written by the developer. These should be approved prior to initial design but may be developed retrospectively after a prototype spreadsheet has been prepared.

The Functional Requirements Document should contain applicable sections to describe:

The intended purpose of the spreadsheet application (such as to calculate results, to re-order results for Management Reports, etc.).
The formulas that will be included in the spreadsheet application, including logical formulas used for branching or for calculations.
A description of macros that will be included.
A description of any column or row rearrangements/sorting that will be required to format a new report from included data.
A description of the report that will be generated.
A statement defining electronic storage requirements for the executed spreadsheet application (results).
Where applicable, issues such as data formats and numerical precision, numeric rules such as rounding or floating points, flagging of limits, boundary conditions, filters or outliers.
Performance requirements for the application and program (i.e., calculations or reports within X seconds, applications/program availability, etc.).
Workflow needs such as the source of the data, a statement regarding raw data, and “who will perform what actions and make what decisions based on what data and criteria” may be required.

5.1.1 Review and Approval of Functional Requirements

The functional requirements should be submitted to the Validation Manager for technical approval, to Quality Assurance for regulatory compliance, the Local Area Network Manager (if applicable) and to the Area Manager for overall approval.

5.2 Spreadsheet Application Development

The Spreadsheet Application Developer will devise the spreadsheet application parameters, such as the way the table looks, data formats, data sorting parameters, the addition of fields to the spreadsheet application, reports, formulas and interfaces with other programs and instrumentation.

5.2.1 Raw Data Considerations

The Spreadsheet Application Developer must define how data will be entered.

Data can be inputted directly from instruments (or data files) into a spreadsheet application or data can be entered manually. For automated operations, raw data will be input directly from the instrument to the spreadsheet application.

If data sets are entered manually, all entered data must be reviewed by a second individual to verify the correctness of the entered (transcribed) data. The initials of the reviewer and the date of review should be indicated.

If data sets are entered automatically through an electronic interface, then the transfer link between the spreadsheet application and the source of the data must be validated.

Similarly, data from a spreadsheet must not be exported to a validated computer system/application unless the transfer link has been validated and the importation approved via change control for the receiving system.

5.2.2 Formula Development

Each formula described in the Requirements Documents must be embedded in the spreadsheet application.

The formulas must be checked for errors during development.

Diagnostic tools that allow error checking to be carried out during development are sometimes available with spreadsheet programs.

Examples of error detection tools include:

· Cell errors – error messages that are created when cell rules are violated

· Auditing tools - Cells which are referred to by a formula in another cell may be audited for alignment, with the spreadsheet displaying tracer arrows between cells

· Error tracer - when a formula returns an error, another auditing tool can be used to track it back to its source

5.2.3 Rearranging Columns and Rows

Spreadsheets are also used to sort and rearrange data for reports and presentations. The source of the data may be from another program/database, or an instrument system such as report data from a chromatographic computer system. The procedures to be used for subsequent sorting or rearranging of the data via the spreadsheet application should be described.

5.2.4 Macro Programming

Frequently performed tasks may be automated by recording them as macros and playing them back whenever necessary. Macros may be associated with toolbar buttons, keystrokes and menu entries. Manual sorting and rearranging of data are actions that might be automated, but if the macro is recorded, the actions must be carefully documented during development and tested during the qualification process.

5.2.5 Report Creation

It is the responsibility of the developer to create/modify the spreadsheet application to report the results of calculations performed by the spreadsheet application.

The Spreadsheet Application Report shall contain:

· The method (analytical if for a lab) used during creation of data

· A unique identifier for the analyst and the checker who are responsible for the correctness of entries into the spreadsheet application

· The date the spreadsheet application was executed

· The version of the spreadsheet application program

· Version control for the report

· The unique name of the electronic version of the file

If data is received through an electronic interface, the report must identify the instrument system or software program communicating the data.

5.3 Qualification Procedure

When the spreadsheet has been developed the file should be transferred to the Validation team

The validation engineer will prepare a suitable test protocol using appropriate template

5.3.1 Installation

The protocol will describe the name, version number, location, control and ensure that appropriate security restrictions are implemented at the time of initial installation to the secure directory.

The Validation Department shall store a master copy of the spreadsheet application in a secure environment. Each time the spreadsheet application is required for use on a computer in the user area, it must be opened from the (read only) master copy. Establishment of Version and Security Control:

The Validation Manager will add the version number and effective date to the spreadsheet application, and lock cells containing formulas to protect the contents of the cells. The spreadsheet application shall be protected by a password. Security Settings:

The Validation Department shall maintain the security information (including the passwords for the spreadsheet application) in accordance with site procedures.

5.3.2 Operation/ Performance

The Operational/ Performance Qualification shall be written to document the instructions for the testing. The Operation Qualification shall include the following tests:

Calculation Test to verify that correct formulas are entered
Logical Values Test to verify Boolean algebra formulas.
Range/Precision Test to verify calculations will still be accurate when extremely large or small values are entered
“Challenge condition” testing for the program and application (e.g., invalid inputs, stress testing)
Boundary and limit checking, failure analysis and confirmation of appropriate error trapping.

Acceptance criteria shall be established for each test and written into the Operation Qualification Protocol. Typical tests with associated acceptance criteria are: Calculation Test

These are performed to verify that correct formulas are entered. Enter sample values in all fields that are included in the input range of all mathematical functions. Restrict the input to whole numbers at this time for aggregate functions (sum, max, etc.) use different values for each field. Document the step, include a printout of the spreadsheet application indicating the test values, and compare the printout to that obtained from a calculator.

Acceptance Criteria

Calculated values from the spreadsheet application must be identical to those obtained from a calculator (preferably with printout capabilities). Logical Values Test

These are performed to verify Boolean algebra formulas. Print the spreadsheet application cells containing Boolean (logical values) and calculate the results manually. Print the results from the spreadsheet application calculation.

Acceptance Criteria

For logical values (e.g. Pass/Fail or True/False) verify the displayed value is the same as the expected value, calculated manually. Range/Precision Test

These are performed to verify calculations will still be accurate when extremely large or small values are entered. Enter extremely large values at the correct precision (e.g. enter 99.99 for 0.01 precision). For aggregate functions, enter 0 in one or more fields with non-zero values in other fields. Duplicate the formula calculations using a calculator and compare the results/printouts. Repeat this test with extremely small values, and report the results.

Acceptance Criteria:

Calculated values from the spreadsheet application must be identical to those calculated manually using a calculator (with correct precision and consistent with agreed Rounding principle).

5.3.3 Execution of Qualification Protocol

Each step of the Operation Qualification Protocol must be appropriately executed and the results recorded.

Testing results and deviations from the protocol will be recorded in an approved documentation system by the Spreadsheet Application Developer.
The testing will be performed by a Spreadsheet Application Developer (or designee).
Test results will be reviewed and approved by the Validation Manager.

5.3.4 Evaluation Requirements

After each step of the qualification process is completed, the following evaluations should occur: Deviations from Protocol:

If the written validation method has not been followed, a protocol deviation must be recorded on the protocol deviation/variance report. An evaluation of the deviation must be completed, and corrective actions listed.

If protocol changes are required, the Protocol Revision Page must be updated as required by the appropriate corporate policy. The revised protocol shall be appropriately approved, e.g., by Quality Assurance and user area Supervisor. Comparison of Results to Acceptance Criteria:

If any of the tests fail, the results must be documented on a protocol deviation/variance report and attached to the executed protocol.

Error analysis shall be conducted and any required changes shall be made to the spreadsheet application to resolve the failure. Typically, all tests must then be repeated. Error Analysis:

If an error results from an incorrect formula, the spread-sheet tools should be used for error analysis to determine the cause of the error. (For example, Excel has error messages for cells and has auditing tools for determining precedents and dependent tracers).

An assessment must be made regarding the impact of the error. Then, if required, the template appropriately modified and all tests repeated.

5.3.5 Final Report

A final report shall be written to summarize the testing results, explain any deviations that occurred during the testing, and to give the rationale for resolution of any deviations. Preparation of Final Report:

The Spreadsheet Application Developer shall complete the Summary of Results Section of the Qualification Protocol, attach all of the associated data and submit the final report for review and approval. Review and Approval:

The Spreadsheet Application Developer should submit the completed Operation Qualification Protocol and associated results for review and approval. The User department manager and the validation manager will review it for technical completeness and the Head of Quality Operations will review for compliance and give overall approval.

5.3.6 Addition to Computer System Inventory:

The Validation Manager shall update the site Computer Systems Inventory List to include the spreadsheet application and validation status.

6 Usage of Spreadsheet Applications

6.1 Availability of Spreadsheet Application:

The Spreadsheet applications shall be protected from unauthorized modification of the master copy. For example, the spreadsheet application shall be available to authorized users as “read only”.

Authorized users will be given access after they have been trained on the use of the spreadsheet application (which shall include proper GMP handling of the files and documentation practices).

Where networks are employed for spreadsheet application use, spreadsheet applications will typically be stored in a network directory that allows access by authorized users. In this instance, the storage of a copy of the spreadsheet application on the hard drive of the local computer shall be forbidden by policy.

6.2 Training of Users

Users shall be trained to use the spreadsheet application. As appropriate, training objectives shall include learning:

· How to use the spreadsheet application, including how to print the Spreadsheet Application Report

· The procedure for storing Spreadsheet Application Reports (if applicable)

Training may be conducted earlier based on a preliminary review of the Final Report.

6.3 Storage of Completed Electronic Files:

When data have been entered into the spreadsheet application, the calculated results become a new electronic file.

If site policy requires storage of an electronic copy of the spreadsheet application file, the file should be stored under a new name in a designated area of the LAN server.

· Files should be named using a convention agreed between the user and site Quality Assurance

· The file name of the completed spreadsheet application electronic report should be recorded in notebook or other similar documentation system as a cross-reference.

· During review of notebook or other similar documentation system data, the reviewer should assure that the electronic file has been stored correctly.

7 Re-qualification of Spreadsheet Application Formulas

Spreadsheet applications in the library will be reviewed / verified every 3 years to address the validity of the validation documentation which includes formula integrity. Reviews will be managed via the Validation Manager program.

Re-qualification may also be triggered by the installation of an upgrade of the spreadsheet program (Change Control System), or by changes in the LAN (e.g., system crashes).

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GMP – Good Manufacturing Practice
It’s Everybody’s Responsibility

The term Good Manufacturing Practice, or GMP, refers to a set of licensing requirements to which companies must adhere in order to obtain and retain a manufacturer license.

In the USA, these GMPs are called current GMPs (cGMPs), and are legally enforceable regulations. Internationally, GMP rules are referred to as codes, rules, or guidance to GMP. (Throughout this module, we will refer to these interchangeably.) Most countries use medicinal regulations that refer to these codes.
• Explain why your company has implemented GMP
• State the purpose of GMP regulations and codes of GMP
• State the four key product quality attributes
• State the GMP requirements for personal hygiene
• Describe the correct way to complete GMP records
• List the essential production and packaging controls

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Guidelines for Regulatory Inspections at a GMP Site:

It is essential that management develop, document and implement procedure(s) for managing inspections by Regulatory Authorities in order to protect the legal rights of the business (and the Regulatory Authorities to perform repeated inspections) and at the same time, to maintain a professional relationship with the regulatory authority conducting the inspection.

Senior Management at a site or function must be present during key parts of an inspection.

Inspection notification, ongoing highlights of the inspection, and the final results of an inspection must be communicated to relevant Senior Management in a timely manner.

There must be a local SOP describing the actions and responsibilities associated with an inspection. The SOP must address the local legal requirements for taking photographs; the use of tape recorders or other electronic equipment; the listening to, reading and signing of affidavits by company personnel; the review of internal audit reports and allowing access to computer databases.

An accurate and detailed record is to be maintained of events, significant comments or recommendations from the inspector(s), documents and / or reviewed/copied for the inspector, product samples, and any other information deemed important to the inspection.

At the conclusion of an inspection, local management must assure that any inspection observations are clearly understood, that any factual errors are brought to the attention of the inspector(s) and that there is a clear understanding of what will be addressed by the site in written communication to the Authority.

Following a detail procedure that can be followed by any GMP site for preparation of inspection by regulatory authority.

The purpose of the procedure is to define the procedure for the conduct of GMP sites employees involved in regulatory authority inspections. This procedure shall be used to guide GMP site personnel in contact or involved with the assistance of any external third party regulatory authority inspection.

It is the responsibility of the Management Representative to implement and maintain this procedure.

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Aseptic Filling Room Personnel Monitoring


To monitor viable organisms on the gloves hands, forearms and uniforms of aseptic filling room personnel.


This procedure applies to the aseptic filling room personnel monitoring at the applicable plant.


It is the responsibility of the Microbiology Department to conduct this SOP as written.


At the beginning and at the end of aseptic filling of every production run (lot), gloved hands of all employees engaged in filling shall be monitored.

Uniforms and forearms shall be monitored once a week.


Sterile blood agar plates or sterile TSA plates, marker, masking tape, Rodac plates and 70% isopropyl alcohol (sterile filtered).


1.Take two sterile blood agar plates or TSA plates; put them on a clean surface. Check the plates (without opening) for any contamination. Do not use if the plates show any contamination. Send all contaminated plates to Microbiology Department for discarding.

2.Aseptically, without spraying your gloves hands with 70% isopropyl alcohol or any other disinfectant, take the lid off from one of the plates.

3.Gently press five-finger tips of one hand (right or left) against the sterile medium in the plate. The pressing should be hard enough to leave visible finger impressions, yet gentle enough not to spoil the smooth agar surface.

4.Repeat step 3 for the other (second) hand.

5.Label each plate with the name of the person whose finger impressions are on the plate, product lot no., which is going to be filled or was filled, start fill or end fill and date. Sanitize hands with 70% isopropyl alcohol.

6.At the end of the production, send all plates to Microbiology Department for incubation.

7.Incubate all plates at 30-35°C for a minimum of 48 hours, along with a negative and a positive control. Prepare a positive control by streaking a plate with the viable culture of Staphylococcus aureus.

8.After incubation, record results on appropriate form (See appropriate form).

Alert Limit:1 CFU per plate
Action Limit:2 CFU per plate

B.Weekly Uniforms and Personnel Monitoring

Uniforms and forearms of all employees engaged in aseptic filling shall be checked for viable organisms by using sterile Rodac contact plates during environmental monitoring of aseptic filling area/rooms. At least one chest print from the center of the chest and one forearm print from each forearm shall be taken.

Handprints of aseptic filling room personnel shall also be taken once a week by microbiology personnel during environmental monitoring.

All plates shall be incubated at 30-35°C for a minimum of 48 hours, along with negative and positive controls. Results shall be recorded on appropriate form (See appropriate form).

Alert Limit:1 CFU/Chest/Arm Print
Action Limit:2 CFU/Chest/Arm Print

C.Weekly Aseptic Personnel Monitoring Upon Exiting Class 10,000 Area

Once a week on one randomly selected day, (e.g. Monday or Tuesday, etc.) uniforms, forearms and handprints shall be checked for viable organisms from all personnel (Manufacturing, Maintenance, Quality Assurance, Microbiology) exiting Class 10,000 area by using sterile Rodac contact plates. At least one chest print from the center of the chest and one forearm and hand from each arm shall be taken. The test shall be performed by either microbiology or production personnel.

All plates shall be incubated at 30-35°C for a minimum of 48 hours, along with positive and negative control. Results shall be recorded on appropriate form.

Limit: develop based upon data.


1. Whenever the count of a filling room employee exceeds the alert limit two consecutive times, the employee shall be retrained for gowning, aseptic technique and CGMPS by the Quality Assurance Department.

2. Whenever the count exceeds the action limit, additional sterility test shall be performed on the product that was filled on that day.

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Market Action Policy at a GMP Site:

Market Action Procedure shall be available at each GMP site that produces, stores or distributes Drug Products, Active Pharmaceutical Ingredients (API) or Medical Device and within each Business Unit responsible for any Market Action activities. The Market Action procedure must be capable of being initiated promptly and at any time. The procedure shall include an outline of actions required to address the following Market Action types as they apply to the markets involved:
• Product Recall,
• Market Withdrawal, and/or
• Field Correction.

Although this procedure applies globally, it is recognized that different and additional local regulatory
requirements may exist. In all such instances, the local regulatory requirements are to take precedence and local Site procedures shall encompass such requirements.

- Any site employee who becomes aware of a situation that might require a Market Action shall report the matter at once to a Supervisor, who shall inform any member of the Site Quality Team or of the Area Quality Review Team.

- Site Management shall be notified of all significant issues that will or might result in a Market Action

- A Market Action Leader shall be identified to coordinate activities necessary to implement a Market Action. A Market Action Leader shall be appointed to represent each country in which the Market Action is conducted. This person must have responsibilities in Regulatory Affairs or Quality Operations and be knowledgeable in the Market Action process and interactions with Regulatory Authorities.

- For recalls conducted in the US and its territories, a Market Action Coordination Committee (MACC) shall be identified. The MACC at a minimum shall consist of the following responsible Center Function principals:
• Market Action Leader;
• Quality Operations;
• Medical Affairs;
• Regulatory Affairs;
• Distribution/Logistics;
• Marketing;
• Country General Counsel (Legal); and
• Media Relations (if information releases are involved).

- For market actions conducted in countries outside the US, activities necessary to implement the market action shall be coordinated by the Market Action Leader for each country (e.g. country Regulatory Affairs principals or Business Unit Quality Contact) with assistance from the GMP Site Quality Team.

- The Quality Team at the Site responsible for manufacturing the product responsible for the
contract manufacturer shall be notified of market actions, conducted in countries outside the US for imported products that are initiated due to local Regulatory Team requirements.

- The concerned Country Regulatory Affairs Managers and Country Qualified Person(s) (QP) shall be informed of and/or involved in any contact or interactions with the country regulatory authorities.

- The Recommendation to Initiate a Market Action, shall be made by the Site Quality Team. The recommendations shall be confirmed in writing by the team meeting minutes.

- For Market Actions in the US, the Market Action Coordination Committee (MACC) shall make the decision whether or not to initiate a Market Action.

- For Market Actions in countries outside the US, the country Regulatory Affairs principals or Business Unit Quality Contact shall make the decision whether or not to initiate a Market Action.

- If the Site Quality Operation (QO) Leader decides to recall a batch (e.g.for personal liability reasons) the decision cannot be overruled by Marketing principals.

- Notification by a Regulatory Team can cause a Market Action to be initiated. In such an event, Site communication with the Regulatory Team shall be through Regulatory Affairs principals and/or the responsible Site Quality Team or Qualified Person (QP). The concerned Country Regulatory Affairs Managers and Country Qualified Person(s) shall be informed of and/or involved in any contact or interactions with the country regulatory authorities.

- Initiation of a Market Action occurs at the time a decision is made that either a Product Recall, a Market Withdrawal, or a Field Correction is required (see Figure 1).

- When the Decision to Initiate a Market Action is Made in the US or its Territories, notification of the Market Action shall be made through QSTS principals via issuance of the MACC minutes or memorandum.

- When a Decision to Initiate a Market Action is Made, Affecting Countries Outside of the US or its Territories, the responsible, Quality Operations Regional Leader (QORL), or Contract Operations Quality Assurance (COQA) Leader, or QSTS representative shall issue a Global Notification to inform the responsible principals representing, at least, the following functions:
• Quality Operations;
• Regulatory Affairs (RA);
• Medical Affairs;
• In Europe, Business Unit Quality Contacts and EU Pharmacovigilance QP, for Market Actions; and
• Other senior management principals (Marketing, Country General Counsel, Sales, Distribution/Logistics, and Supply Chain Management).

- Upon receipt of the Global Notification, each country RA principal and/or Business Unit Quality Contact shall decide if additional notifications to country Regulatory Authorities are required. This decision shall be documented in accordance with local regulatory requirements.

- If a Market Action will result in an interruption to the supply chain, the relevant country Regulatory Authorities shall be notified by the country RA principal and/or Business Unit Quality Contact.

- Periodic Reports of the Market Action Status, when required by regulations, shall also be issued to inform the Regulatory Authorities of the Market Action progress. The Market Action Leader shall ensure that a Final Report of the Market Action, including reconciliation between the delivered and recovered quantities of product, shall be prepared, when required by regulations.

- Site Principals shall periodically evaluate the effectiveness of, and preparations for implementing the Market Action procedure by conducting a mock Market Action to Verify adequacy of their local procedure and training of related personnel. Mock Market Actions shall be performed in accordance with a time period specified in the Site’s local procedure, unless a real Market Action had occurred in the same specified time period. Records of such evaluations and audits shall be maintained.

- For human health products marketed in the US and its territories, QSTS shall assume responsibility for performing a mock recall when required.

- A Specific Market Action Strategy shall be prepared by the Market Action Leader(s) for each Market Action initiated, defining actions to be taken in each affected country. The Market Action Strategy must include, at least, the following:
• Type of Market Action;
• Depth (i.e., level of product distribution) of the Market Action (e.g., wholesale, retail / pharmacy, patient);
• Classification of the Market Action based on the potential health risk;
• Method of customer or public notifications; and
• Extent of Market Action Effectiveness Checks, if required by regulations.

- The Market Action Leader(s) shall also arrange for this strategy to be reviewed and Approved by the Regulatory Team when required by regulations.

- The Seriousness of a Potential Health Hazard is determined by Medical Affairs and/or Safety principals and is communicated to the country RA principals, who will provide the information to
the impacted country Regulatory Authorities for consideration in classifying a Product Recall.

- Accurate, Detailed Inventory and Distribution Records of APIs, medical devices, and drug product Lots or Batches must be made readily available to the MACC or, Country Regulatory Affairs Manager or Business Unit Quality Contact to facilitate a Market Action. Responsibility for providing this information to these principals lies with the personnel responsible for managing Distribution / Logistics Services, Depots, and Supply Points.

- Product Lots Involved in a Market Action must be physically isolated and placed in designated areas.
Final responsibility for lot/batch Disposition is vested with the Site Quality Team.

- For Contract Manufacturers Involved in a Market Action, the Director/Team Leader Contract Operations Quality Assurance (COQA) and/or the responsible Site Quality Team shall
serve as the primary liaison between the responsible Market Action Leaders and the contract manufacturer.
- When Public Information Releases are required, a draft shall be sent to the applicable Country General Counsel (Legal), Regulatory Affairs, Business Unit Quality Contact, Marketing,
Medical Affairs, and Media Relations for review and authorization.

- Effectiveness Checks, when required by regulations, shall be conducted to verify that customers have received Market Action notifications and have taken the specified action.

- A Market Action Final Report shall be prepared by the Market Action Leader and issued as defined by the Market Action Procedure at the completion of the Market Action to, at least, the following:
• Regulatory Authorities; and
• Responsible management principals [e.g., Quality Operations, Regulatory Affairs, Medical Affairs, Qualified Person (QP), Marketing, Country General Counsel].

- Market Actions shall be considered in a number of situations including, but not limited to, the following:
• Results of a Product Complaint Investigation,
• Review of product retention samples of a distributed product lot,
• Material erroneously released to stock without Quality Team authorization,
• Mislabeled marketed product,
• Failure of a marketed product lot to meet Specifications, or
• Request or mandate from a Regulatory Team.

- When a Potential Market Action is Identified, a Stop Distribution Notice (SDN) shall be issued for all affected lots and the affected lots shall be placed under Quarantine-Hold status.

- The Market Action Leader in conjunction with the Site Quality Team is responsible to ensure the following activities are completed:
• Inform and/or involve the concerned Country Regulatory Affairs Managers and Country Qualified Person(s) in relevant Market Action activities;
• Consultation with Regulatory Authorities, in country of manufacture and country of distribution, on Market Action activity;
• Identification of the product and Lot Numbers involved and the time period when the affected lot(s) was/were distributed;
• Preparation of the draft Market Action communication;
• Preparation of the draft public information releases for review by applicable Country General Counsel (Legal), Regulatory Affairs, Business Unit Quality Contact, Marketing, Medical Affairs, and Media Relations;
• Notification of Site Global Research and Development principals of Market Actions, which could affect clinical studies;
• Coordination of Market Action communications;
• Determination of the depth (i.e., level of product distribution) of the Market Action (e.g., wholesale, retail/pharmacy, patient);
• Verification that a complete record of all returned material is maintained by the receiving locations;
• Determination of the method and level of Effectiveness Checks, as required;
• Preparation of all status reports, where required and final reports related to the Market Action;
• Maintenance of records of all Site-related Market Actions in accordance with established record retention standards and procedures;
• Verification of proper disposition of returned product; and
• Coordination and/or execution of Effectiveness Checks as required.

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API - Impurity Profile Generation


This SOP addresses those impurities in drug substances classified as degradation products of the active ingredient, impurities present in the drug substance as part of the manufacturing/storage process or reaction of the drug substance with an immediate container/closure system.


A.Foreign substances: Materials introduced by contamination or cross contamination and are not consequences of the preparation of the drug substance.

B.Residual Solvents: Organic volatile chemicals that are used or produced in the manufacturing process. The solvents are not completely removed by practical manufacturing methods. Drug products should contain no higher a level of residual solvents than can be supported by safety data. For a classification of residual solvents, refer to the current USP <467>.

C.Toxic Impurities: Impurities that have significant undesirable activity. These require individual identification and quantitation by specific tests.

D.Concomitant Components: These are characteristic of many drug substances. Examples may include, but are not limited to, geometric and optical isomers or racemates.

E.Signal Impurities: Impurities that require individual identification and quantitation by specific tests. Signal impurities may include some process related impurities or degradation products that provide key information about the process.

F.Ordinary Impurities: Impurities that are innocuous by virtue of having no significant, undesirable activity in the amounts present. These impurities may arise out of the synthesis, preparation or degradation of the drug substance. For further information, refer to the current USP <466>.

G.Related Substances: These impurities may be identified or unidentified degradation products or impurities arising from the manufacturing process.

H.Degradation Study: A means of degrading a drug substance via several routes, usually involving acids, temperature, light, etc., in order to evaluate the routes and base of impurities. This information is used to generate the impurity profile of the product.

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Calibration Master Plan


1.1The purpose of the Master Calibration Plan is to define the requirements necessary for establishing and implementing an effective Calibration Control Program. The aim of the Calibration Program is to ensure that all Measuring and Test Equipment (M&TE) included in the program are calibrated to within the manufacturer’s accuracy specifications or to the tolerances required by the application. Documented trace ability to either the National Institute of Standards and Technology (NIST) or other applicable agency must be maintained.


2.1Quality Assurance Personnel:

2.1.1QA Personnel will establish a mechanism for assuring the adequacy of the calibration program that includes:

-Re-evaluation of all product acceptance decisions utilizing equipment or instrumentation which was subsequently determined to be out-of-tolerance.

-Review and approval of decisions to include or exclude M&TE into the calibration and/or service program.

-Review and approval of calibration and/or service intervals.

-Review the adequacy of measurement accuracy for product/process/process acceptance and adjustments of product acceptance limits, or other
actions required to assure adequate measurements.

-Audit the calibration system and M&TE usage to assure compliance with the intent of this document.

-Review to ensure that product specification changes, new accuracy requirements, and current GMP requirements have been included in the

calibration program.

-Review calibration agency performance to assure appropriate technical levels are maintained.

2.1.2Responsible for auditing appropriate functions for compliance to this protocol.

2.1.3Responsible for assuring that program action items identified in this document are implemented.

2.1.4Responsible for assuring that all metrology personnel have the proper training and that documentation of the training is kept on file.

2.1.5Responsible for final approval of all documents relating to metrology department.

2.1.6Responsible in tracking document revisions and assuring that all documents in use are current.

2.2Metrology Personnel:

2.2.1Responsible in implementing the Calibration Program.

2.2.2Responsible for developing and maintaining a controlled

2.2.3Metrology Standards Laboratory to support the ongoing cGMP processes at the Facilities.

2.2.4Metrology and Facilities personnel will be utilized to support all departments, using M&TE, within the company, wherever possible. Outside calibration agencies may be used at the discretion of Metrology, provided that the calibration agency has been pre-audited by Metrology and/or QA and found to be in conformance with this document.

2.2.5The calibration program must be strictly adhered to and “down-time” of equipment must be kept to a minimum.

2.2.6Accountable for notifying Production and QA personnel of any discrepancies found in instrumentation during routine maintenance and calibration. All discrepancies must be recorded on a GMP Incident Report which must then be forwarded immediately to the QA Manager.

2.2.7Metrology and QA shall evaluate the procedures outlined in this protocol annually. This evaluation will include monitoring and updating to ensure compliance with cGMP’s.

2.2.8Production equipment and calibration programs shall be strictly adhered to and “Down Time” of equipment will be kept to a minimum.

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A pharmaceutical manufacturing plant compliant with Good manufacturing Practice must have cleaning validation program in place to establish documented evidence that the cleaning processes will consistently ensures that the products produced will meet expectations for purity, identity, safety and quality. The purpose of cleaning validation is to ensure that no significant amounts of active ingredients or excipients carry over into subsequent uses of the equipment.

Cleaning procedures are established in order to eliminate or reduce cross contamination between products, cleaning agents and microbial contamination to acceptable levels. The cleaning procedures define the frequency of cleaning, the cleaning method, the type and concentration of cleaning agents used or the automatic cycles employed for Cleaning In Process (CIP) systems.

Applicable equipment qualifications and all supporting method validation must be completed prior to execution of cleaning validation studies.

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The basic concepts of Quality Assurance (QA), GMP and Quality Control (QC) are interrelated. The sum total of all these entities together comprises the pharmaceutical quality system (PQS). The functions or roles of QA, GMP, and QC are collectively critical to the effective and safe production and control of medicinal products.

Pharmaceutical products must be manufactured according to well-established GMP rules. These GMP rules have been developed over the last 50 years and are based on practical experience and accumulated knowledge in the industry.


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Customers of pharmaceutical products expect products that are safe and effective. One of the ways to ensure that products ore safe and effective is by producing finished products that ore correctly identified. Product and labeling mix-ups can result in potentially serious consequences.

As such, GMP rules require that products rules be correctly identified with the correct name, ingredients, strength, and botch information. There must be no unspecified components present.


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