Non sterile process Validation

1.0 Introduction

• Process validation data should be generated for every product during manufacturing process. It should be in accordance with GMP principles. The data should be available for inspection at the manufacturing location.
• The collection and evaluation of data should be done throughout the life cycle of product from design stage of a product to stage where it is available for commercial production.
• Risk management approach should be done by assessing the risk and the extent to which it can impact the product.
• Based on relevant studies the steps for combating the risk and the key parameters should be given. These critical parameters should be monitored throughout the cycle.
• A flow diagram can be given depicting its operations and controls. Any changes made to the diagram should be recorded from time to time.
• Manufacturers should make sure that the principles are followed as described at various phases like design, scale up, qualification of equipment’s, utilities, premises and process performance.

1.1 Objective

• The objective of the process validation is to evaluate the process so it is reliable, reproducible and robust. The commercial manufacturing process should be defined, controlled and monitored. The process should be assured so that it stays in controlled state.

1.2 Scope

• The guidelines given by WHO and ICH are for non-sterile finished pharmaceutical dosage forms. QRM principles are to be followed throughout the process with a life cycle approach. Process analytical technology (PAT) is used to ensure that process is in controlled state during manufacturing

1.3 Approach

• Various approaches are given for validation of process.
• Traditional approach comprises of prospective and concurrent validation.
• Historical data is evaluated if there are any changes in the process done previously.
• New approach includes three phases like process design, process qualification and continued process verification along with risk management, change control.

1.3.1 Process design

• Product development activities include key inputs like dosage form, quality attributes and manufacturing pathway.
• Pilot scale or laboratory models are designed representing the process to estimate the variability.
• It should include experiment design, process development, and manufacture of products which are used in clinical trials, technology transfer and pilot scale batches
• Process design should also cover criteria for selection of materials, variations which may happen in production, qualification of unitary process, selecting production technology or process which comprises the manufacturing process.
• For the control strategy selection of in process controls and tests, inspection and their suitability
• Some validation studies are conducted on pilot scale batches of production scale.
• Along with process design, process qualification and process verification should be linked referring the specific batches which are used in critical development of product.
• A technology transfer or development report is to be prepared by review and approval of R&D personnel. It should be accepted by quality, manufacturing and engineering personnel.
• The document should include information on clinical performance, suppliers, bill of materials, QTPP, product specifications and test methods, quality attributes, critical process parameters, data on stability batches, formulation batches, scale up batches, clinical or bio batches, stability reports, critical quality attributes. 
• The document should be available in the manufacturing site.
• The ultimate aim of the process should be to deliver consistent product which meets quality attributes.

1.3.2 Process qualification

• Premises, equipment, utilities, support systems and personnel should be qualified before validating the manufacturing process.
• During validation methods, apparatus, measuring systems, environmental controls should be considered.
• The stages include design, installation, operation and equipment performance.
• Even though three batches are considered, the number of batches should be based on risk assessment.
• Manufacturer decides at which stage the process is validated and justifies it. This decision should justify number of batches based on variability and complexity of the process.
• For commercial distribution successful completion of this stage is important.
• Risk assessment should be performed from scale up to commercial batch size. This stage should ensure that scale up in batch size doesn’t impact the product characteristics and meets the defined parameters.
• Extensive inline or online controls should be used to monitor the process performance and its quality. Results should be collected on verification of parameters, attributes, end points and trends of process parameters (CPP).
• New validation approach can be implemented by the manufacturer if the processes are known and of acceptable capability.

Validation should be done according to the process validation protocol; this protocol should include the following:

• Manufacturing conditions
• How the data is collected & evaluated
• Testing or monitoring activities along with the acceptance criteria
• Sampling plan
• Number of batches considered
• Description of Statistical tools and models
• Process description
• When, where, how and how many or how much sample is to be considered
• Product performance characteristics
• Acceptance limits
• Responsibilities of the personnel
• Methods for recording and evaluating results

Data should be evaluated according to the predetermined criteria and documented

1.3.3 Continued Process verification

• After the process design and process qualification the quality of the product should be monitored by the manufactures.

Scope and extent of the this stage is governed by the following factors

• Prior knowledge on development and manufacturing of similar products
• Understanding of the process from commercial manufacturing experience and development studies
• Complexity of product or process
• Automation levels and analytical methods used
• Any products with similar product life cycle
• The verification strategy should be given by the manufacturer about its feasibility and appropriateness along with process parameters, material attributes and analytical methods
• The following should be defined by the manufacturer
• Testing or monitoring method
• Acceptance criteria
• Evaluation of data and actions taken
• Statistical methods or tools description
• Trends on quality of the materials or components

1.3.4 Change management    

When any changes are made then change control procedures should be followed

• Change control procedures should ensure that all aspects are documented and approved by the regulatory authorities
• Data should be generated so that the product is of desired quality and in compliance with specifications
• When any changes are made in production then control procedures are executed
• Change control procedures are based on risk assessment.

The following require revalidation when changes occur in

• Master formula, methods, starting materials manufacturing and process and excipient manufacturing and process
• Equipment’s, support systems and instruments   
• Equipment calibrations and preventive maintenance
• Production area   
• Manufacturing process
• Transfer of processes to different site
• SOP
• Cleaning and sanitization programmes
• Unexpected changes

1.3.5 Related Documents

http://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex3-TRS992.pdf

Non sterile process validation, good manufacturing practices, risk management, process design, process qualification, continued process verification, change management, change control