Process Validation: General Principles (USFDA)
This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes. FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle.
The lifecycle concept links product and process development, qualification of the commercial manufacturing process,and maintenance of the process in a state of control during routine commercial production.
Process ValidationDefinition (1987 ) :
“Establishing documented evidence which provides a high degree of assurance that a specific process
will consistently produce a product meeting its predetermined specifications and quality characteristics”
Process ValidationDefinition (2011 ) :
“The collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products”
Process Validation and Drug Quality
Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use.
This principle incorporates the understanding that the following conditions exist:
- Quality, safety, and efficacy are designed or built into the product.
- Quality cannot be adequately assured merely by in-process and finished-product inspection or testing.
- Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications.
Approach to Process Validation:
Process Design: The marketable manufacturing process is defined during this stage based on
knowledge gained through development and scale-up activities
Process Qualification: Throughout this stage, the method design is estimated to determine if the
process is capable of reproducible marketable business.
Continued Process Verification: Constant assertion is gained during routine production that the
process remains in a state of control.
A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process
Stage1: Process Design:-
Constructing and Apprehending Process Knowledge and Understanding:
- The functionality and limits of commercial manufacturing equipment should be considered in the
- Design of experiments (DOE) studies can help to develop process knowledge by revealing
relationships, including multivariate interactions, between the variable inputs and the resulting outputs.
- Risk analysis tools can be used to display possible variables for DOE studies .
FDA expects controls to include both examination of material quality and equipment monitoring. Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios:
- When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) .
- When intermediates and products cannot be highly characterized and well-defined quality
attributes cannot be identified.
Creating an Approach for Process Control:
- Controls and consist of material analysis and equipment monitoring at significant.
- hese controlled records are established in the Master formula records and control processing points.
- The calculated commercial production and control records should be carried forward to the next stage
Stage 2: Process Qualification:-
Element (1): Design of a facility and qualification of utilities and equipment
- Ensure qualification of facility, utilities, and equipment is completed & documented prior to initiate
Element (2): Process Performance Qualification (PPQ)
- The PPQ combines the actual facility, utilities, equipment’s and the trained personnel with the
commercial manufacturing controls.
- A company must successfully complete PPQ before commencing commercial distribution of the drug
- To understand the marketing process adequately, the manufacturer will need to consider the effects of
- Strongly recommend firms employ objective measure (e.g. Statistical Metrics) wherever feasible and
meaningful to achieve adequate assurance.
- The increased level of inspection, testing, and sampling should continue through the process
verification stage as correct, to establish levels and occurrence of routine sampling and checking for the
particular product and process.
- Considerations for the duration of the intensified sampling & checking period could include (not
- Volume of production
- Process Complexity
- Level of process understanding
- Experience with similar products and process
Qualification of utilities and equipment generally includes the following activities:
- Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.
- Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).
- Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage,and start-up as is expected during routine production.
- Operating ranges should be shown capable of being held as long as would be necessary during routine production.
Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The plan should identify the following items:
1. the studies or tests to use,
2. the criteria appropriate to assess outcomes,
3. the timing of qualification activities,
4. the responsibilities of relevant departments and the quality unit, and
5. the procedures for documenting and approving the qualification.
Some of key elements to be captured in validation protocol as detailed below;
- Manufacturing conditions, including operating parameters, processing limits, and raw material inputs.
- Test to be performed and acceptance criteria for each significant processing step
- Sampling plan (sampling points, number of samples, frequency of sampling)
- No. of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches.
- Status of the validation of analytical methods used is measuring the product.
- Provision for addressing deviations
- Approval of the protocol by appropriate department
- Compression RPM (low, medium, target) is not recommended in protocol.
- Batch records does not provide any detail about the RPM which are not worked
- Currently followed
- Sampling points not pictorially depicted (however SOP reference is mentioned)
- Between the batches?
- Currently not followed
- Currently followed
- Currently followed
- Validation shall be executed as per validation protocol duly approved by Quality unit.
- To state a clear conclusion as to whether the data indicates the process meets the conditions established
in the protocol. If not the report should state what should be accomplished before such a conclusion can
- This conclusion should be based on entire compilation of knowledge and information gained from the
design stage through the PPQ stage.
Stage 3: Continued Process Verification:-
- To confirm that “the process remains in a state of control during commercial manufacture.”
- An ongoing process to collect and analyze product and process data that relate to product quality must
- The results obtained should be statistically trended and reviewed by trained personnel.
- Recommend that a person with suitable training in statistical process control techniques develop the
data collection plan and statistical methods.
- Good process design and development should anticipate significant sources of variability and establish
appropriate detection, control and or qualification schemes, as well as suitable alert and action limits.
- Study of intra-batch as well as inter-batch variation is part of a comprehensive continued process
- Deviation can be detected by the timely assessment of Defect complaints
- OOS findings
- Process deviation report
- Process yield variations
- Batch record & reports
- Manufacture line operatives and quality unit staff should be encouraged to provide feedback on process
- Quality unit meet periodically with production staff to evaluate data, discuss possible trends and
coordinate any correction or follow-up actions by product.
- Data collected during this stage might recommend ways to improve and/or optimize the process by
altering some aspect of the process or product, such as the operating conditions, process controls, etc.
- Well justified rationale for the change, implementation plan, quality unit approval before
Concurrent Release of PPQ batches:
- FDA expects that simultaneous release will be used rarely.
- Circumstances and reasoning for simultaneous release should be fully described in the PPQ protocol
- System of careful oversight of the distributed batch to facilitate rapid customer feedback.
- Documentation at each stage of the process validation lifecycle is essential for effective statement in
difficult, lengthy, and multidisciplinary projects.
- Documents is important so that knowledge gained about a product and process is accessible and comprehensible to others involved in each stage of the lifecycle.
The degree and type of records required by CGMP vary during the validation lifecycle.
- Records requirements are greatest during Stage 2, process requirement, and Stage 3, continued process confirmation.
- Studies during these stages must conform to CGMPs and must be approved by the quality unit in accordance
with the regulations (see §§ 211.22 and 211.100).
1. FDA (CDER and CBER), Process Validation: General Principles and Practices, Current Good Manufacturing Practices (CGMP), Revision 1,January 2011.
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube