Process Validation Update.

Image of process validation of GMP controlled pharmaceuticals.

The new Process Validation Guidance publication: General Principles & Practices introduces a life cycle approach to process validation. While the guidelines no longer think the use of traditional three-batch validation appropriate, it does not stipulate the number of validation batches appropriate for a prospective validation protocol, nor does it provide a rationale to determine it. This could; and has, left many manufacturers in a dilemma

The way forward must be by utilizing a continuing activity that constantly verifies  process compliance?

The secret to success is going to be in selecting the single parameter robust enough to be used as yard stick for the process efficacy.   Once this can be achieved preventative measures will become routine practice as operators use predictive analysis to execute routine maintenance - before product drifts out production tolerances.  The whole process life cycle can be monitored with  suitable data capture systems.  Which will be be used in product release and simplification of end-product release analysis?

Developing Continuous Process monitoring.

Process validation stats schematic.

Statistical Process Control (SPC).

PC systems use statistics to monitor the quality of products created by a process and send alerts when something abnormal is detected.  Control charts are pretty good at showing when a process is behaving normally and are usually the first step in controlling quality.

Run-to-Run Control (R2R).

R2R control involves the use of measurement data to optimize a particular process step or set of steps  This is an example a feedback control system.  R2R control systems generally start off controlling a single process but can be grown to achieve factory-wide control solutions.

Fault Detection and Classification (FDC).

FDC systems monitor the performance of manufacturing equipment during operation and detect events that might affect the quality of the product.  When an issue is detected a warning message is raised.

Advanced Process Control (APC).

APC brings together all of these pieces of software.  In a fully realized APC system, each component (SPC, R2R, FDC) can interact with the others to form a comprehensive factory control system.

Process Validation (PV)

Image of pharmaceutical product subjected to process validation.

For Process Qualification to be successfully executed then critical quality characteristics and critical process parameters must be derived from research and development scale-up, or existing commercial production history. If these parameters do not exist, it is necessary to establish them through either designed experiments or planned review of commercial history prior to the start of validation.

Although often combined in the same protocol, the purposes of PQ and PV for products differ. PQ starts to address the ruggedness of each of the process steps.  While PV puts all the parts together to verify that the process can consistently and accurately be replicated..

The performance of certain support processes can be proven for multiple products without having any product involved. Examples of these include sterilization of stoppers and glassware, aseptic processes, and cleaning validation. The specifics of these are discussed in other chapters.

Determining Critical Process Parameters

Operator engaged in process validation execution.

This section will briefly discuss the determination of critical process parameters, since the establishment of critical process parameters is one of the mast important pre-requisites for PQ / PV. In general, the primary objective of each unit operation is identified as it relates to the critical quality characteristics of the product. Acceptance criteria are defined for the critical quality characteristics based on the allowable variation in the process step, relevant to its location in the process. That is, steps become more important as the process moves closer to the bulk drug substance and drug product since there are fewer opportunities to improve product quality.

A risk assessment, based on the margin between the normal operating range (NOR) and the proven acceptable range (PAR), should be performed to evaluate the likelihood that a parameter will cause batch failure. If the parameter is deemed to have a high likelihood to cause hatch failure and it is a difficult parameter to control, it is deemed critical.  In other words, the normal operating range is close to the proven acceptable range. If the risk is low because the proven acceptable range is relatively large and the parameter is easily controlled, the parameter is still of interest, hut it does not need to be evaluated during validation. These are deemed “quality” or “important” parameters”.

Prospective Process Validation.

New operative being tutored for process validation purposes.

Prospective validation involves manufacturing, sampling, and testing validation batches according to a pre-approved test protocol Validation batches are not released until all batches specified in the protocol have been manufactured, all tests have been executed, all results have been reviewed, deviations addressed, all acceptance criteria are met, test reports have been written and approved and all change requests have been closed. The system owner must justify any exception to the above conditions and the justifications must he reviewed and approved by QA.

Pre-Requisites to Start PQ and or PV.

Image new operator process validation acceptance training.

The following is a checklist of knowledge that must be available prior to starting PQ and/or PV:

·            Critical Characteristics & associated limits must be established

·            Critical parameters & associated limits must be established

·            Rationale for non-critical process parameters

·            Process description and process drawings

·            Equipment and materials requirements

·            Proposed hatch records and standard operating procedures

·            Initialization of cleaning validation.

·            Recommended in-process controls.

·            Data to support upper control limit and lower control limit.

·            Validated analytical methods

·            References to development studies

·            Reference to previous validation, if any

·            PQ/PV protocols available prior to execution.


Validation Scope.

Image freeze drying process validation.

Before reaching the conclusion that a process validation has been successfully completed, it is necessary to demonstrate that the specified process has not adversely affected the finished product. Where possible, product process verification testing should include testing under conditions that simulate actual use. Product process qualification testing should be conducted using product manufactured from the same type of production equipment, methods and procedures that will be used for routine production. Otherwise, the qualified product may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets the pre-determined specifications and quality attributes.


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Equipment combined IQ/OQ/PQ Protocol.   $159.00

This combination protocol has been produced in response to several hundred reader suggestions we received in our ‘Suggestions Section’. It has been carefully designed to make it the preferred choice for Process and Laboratory stand alone equipment. It is interactive, easy to use and suitable for all mixes of equipment with and without software.
The IQ section establishes documented verification that key aspects of the equipment adhere to approved design intentions and that the recommendations of the manufacturer have been suitably considered. The OQ section establishes that there is documented verification that the installed system functions as specified and that there is sufficient documentary evidence to demonstrate this. The PQ section gives documented verification that the equipment performance in its normal operating environment is consistently exactly as specified in the URS.


12000002_VrrP_Equipment_iss-4. -- $298.00

This Validation, Risk & Requirements Plan (VrrP) is one document designed specifically to replace three. The contents of the three original documents were completely revised and edited into a more compact and interactive format.  This new format will make a very significant difference to the man hours required to produce and execute these documents.  There will also be a very noticeable reduction in the time required for the reviewing and approving tasks.  This new document titled the VrrP replaces the VP, VRA & URS and now compliments our equally new 4Q Protocol, which integrates the DQ/IQ/OQ/PQ into one document. 
This is an essential step forward for companies seeking to reduce validation costs without infringing regulatory standards.


12000006_4Q_Equip_iss-4. -- $298.00

4Q Equipment Validation Protocol (4Q-Equip) has been designed specifically to replace four standard protocols.   By taking the contents of the four protocol and carefully weaving them into one notably easy to use protocol, we have made a significant advance in the task of streamlining validation documentation by reducing protocol numbers by close to 75%.  The new bang up to date 4Q protocol replaces the DQ, IQ, OQ & PQ and now compliments our equally new VrrP Protocol.  By integrating the old style DQ/IQ/OQ/PQ into one 4Q document there will be enormous savings in man hours in the authoring, reviewing, updating and approving tasks.
For everyone's convenience, it is still written in word.


Design Qualification (Issue 5) -- $115.00

The Standard Operating Procedure attached to this generic design qualification protocol, will chapter by chapter, take you through the task of raising a fully detailed document. The main body is split into fourteen tables, each one probing the design requirements and standards for the individual requirement. Safety and security along with user operability are very detailed. The document will lead you through all these design aspects allowing you to delete some you feel are not important to your equipment. It is an easy document to use and will ensure that you’re DQ’s are relevant, up to date and easy to execute. Practically all the requirements are in table form. Allowing fast and clearly presented results to be obtained.


Performance Qualification (P1Q) (Issue 5.) -- $89.00

The Performance Qualification is the last of the qualifying tests that equipment and processes are subjected to, prior to the actual first product run. It maybe that there are some steps in the process that can only be verified by actually running them (quick freezing and sublimation, to mention only two) or it somtimes is the fact that the product is a very expensive product, and can not be wasted. So no one wants to run the process with product, until they are completely certain there will be minimal waste.