Pharmaceutical Process Validation: An Industrial Perspective

 

Sai Kiran A. Dara*, Ravi N. Tiwari

 

ABSTRACT:

Quality is the primary reason for the industry for the products manufactured and validation has therefore become one of the most debated topic of recent times. Validation means confirming that a system or a product caters to its predetermined specifications so that the quality and safety of the product is ensured. It utilizes statistical tools for the analyses of the process logically so that a process is designed in a suitable manner that gives enough assurance that the product is consistent in quality throughout its lifecycle. Earlier, Process Validation (PV) was considered as a burden as it was thought that PV was only a regulatory requirement and was criticized by many. But, literature from previous three decades state that pharmaceutical process validation has evolved and now it is well accepted and regarded as a part of total quality and process management. Validation development is do so that the particular process delivers the product with its predetermined quality attributes and hence validation has become one of the regulatory perquisite for the grant of their manufacturing and marketing authorizations. Hence PV is one of the integral part of quality assurance and this article emphasises on process validation and its types, lifecycle approach and merits of PV.

 

 

INTRODUCTION:

Pharmaceutical Process Validation (PV) is one of the most controversial aspects of recent times. The origin of validation activities in the global healthcare industry can be traced to terminal sterilization process failures in the early 1970s¹. The goal of development is to identify the process variables necessary to ensure the consistent production of a product or intermediate. The current guidelines from US Food and Development Administration (FDA) incorporated the life cycle approach of PV³. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control ^4. These guidelines include some typical alterations in the practice of Active Pharmaceutical Ingredient (API) production based on their extensive research, experience and inspection. FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems in manufacturing process lifecycle⁸. The goal of Pharmaceutical industry is to simplify validation without sacrificing the quality of the product³.

 

PV is one of the most crucial parameters of current Good Manufacturing Practices (cGMP). The regulation of Quality System (QS) details the requirements of the PV with the objective of consistent production of products fit for intended use⁵. PV establishes the flexibility and constrains of the manufacturing process controls in attainment of desirable attributes while preventing the undesirable attributes of drug products ⁶.  Drug Regulatory Authority (DRA), Ministry of Health requires the complete documentation of PV along with other required files for the grant of Marketing Authorization (MA). PV also aids the manufactures in understanding the Quality Management System (QMS) requirements concerned. The FDA, under the authority of existing CGMP regulations, guidelines and directives, considers process validation necessary because it makes good engineering sense⁷.

 

The most usually used definitions of PV are given US FDA, European Medicines Agency (EMEA). The definitions are listed as follows:

 

By US FDA,

Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product⁸.

By EMEA,

Process validation can be defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes⁹.

 

The current guidance coordinates process validation activities with a product lifecycle concept along with existing FDA guidance, International Conference on Harmonisation (ICH) guidance for industry, Q8 (R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. This approach maintains the process in state of control throughout commercial production with respect to method development and product, qualification and maintenance⁸. The rationale behind the practice of validation is an important component o GMP and hence Quality Assurance ².

 

Classification of Pharmaceutical Validations

The field of validation is further divided into various categories as a wide variety of activities, processes, procedures, equipment’s etc. have to be validated and includes¹⁰:

ü  Facilities Validation

ü  HVAC System Validation

ü  Equipment Validation

ü  Process Validation

ü  Analytical Method Validation

ü  Cleaning Validation

ü  Computer System Validation

 

Objective and Scope of Process Validation

PV is the function of Quality Assurance (QA) that helps to ensure drug product quality by providing documented evidence that the manufacturing process consistently does what it purports to do. Validation controls the process and hence process control is demonstrated with satisfactory repeatability. Three simultaneous successful process runs ensure repeatability.

 

The master formula of a particular product’s manufacturing procedure has to be validated and revalidated if there is any change in the ingredients, manufacturing process, packing material or any other composition³.

 

Basic Principles¹³

The underlying principles of validation can be stated as follows:

Installation Qualification (IQ):

It is establishing documented evidence that all aspects of the facility, process, equipment and ancillary systems adhere to the given manufacturer’s specification and are appropriately installed.

Documentation of IQ should include:

• Design features of equipment (Ease to clean the equipment machinery)

• Calibration, cleaning schedules and Preventive maintenance

• Drawings, layouts, documentation etc. from supplier

• Installation conditions (wiring, functionalities etc.)

• Software documentation

• List of ancillary components

• Safety Characteristics

• Environmental conditions (humidity, temperature and other requirements)

 

Operational Qualification (OQ):

It is establishing documented evidence that all aspects of the facility, process, equipment and ancillary systems which can affect the product operate within the approved predetermined specifications. In the OQ, tests are performed on the critical parameters of the system/process ¹⁴.

Documentation of OQ should include:

• Control Limits of the Process (temperature, pressure, speed, time etc.)

• Raw Material Specifications

• Change Control of the Process

• Training to Personnel

• Operating Procedures of the Process

• Stability and Sustainability of the Process

• Requirements of Material Handling

• Worst-case scenarios, Actions to be taken etc.

• Software parameters

• Use of Valid Statistical techniques for process optimization

 

Performance Qualification (PQ):

It is establishing documented evidence that all aspects of the facility, process, equipment and ancillary systems consistently to produce the product meeting all the predetermined requirements.

Documentation of PQ should include ²²:

• Actual process, product parameters and procedures established in OQ

• Assurance of process capability as established in OQ

• Acceptability of the product

• Repeatability of the process and its stability on long-term basis

 

Re – Qualification:

It means ensuring that the equipment is in the state of control after any changes or certain time period and periodic assessment of the equipment within defined intervals is called re-qualification. This should be done with proper review and documentation has to be done. The review should summarize the need for re-qualification. The Preventive Maintenance Program and Documentation system is required to handle small alterations with no direct effect on final or in-process product quality.

 

 

Decision tree

The following flow chart may be useful in the decision making of the process¹³:

 

Figure: 1 Process validation Decision tree

 

 

 

Steps Involved

Based on the method being developed there are various steps of PV. Nevertheless, the general steps followed in PV include¹⁰:

ü  Definition of the plan and method development.

ü  Background verification

ü  Method Development at Laboratory scale

ü  Development of test procedure

ü  Definition of methods in Validation Protocol

ü  Development of validated methods

ü  Validation reports

 

Stages of Process Validation

Process Validation is collection and evaluation of data, from the process design stage to commercial production, which establishes scientific proof that a process is capable of consistently producing quality product. Life cycle of Process Validation involves a series of activities. These activities can be categorized into three stages:

I)        Process Design:

The commercial process is defined during this stage based on the knowledge obtained through process development and scale up activities ¹¹. Research and Development and other related studies are done in this stage.

 

II)      Process Qualification:

The process design is confirmed as it is capable of reproducible commercial manufacturing during this stage. It affirms that all the limits of Critical Process Parameters (CPP) are valid and it will produce acceptable products even in worst case situations. It also necessitates the qualification of the facility, equipment and utilities ²³.

 

The process qualification stages covers:

• Design of the facility and qualification of equipment

• Performance qualification

• PPQ (Process Performance Qualification) protocol

 

III)    Continued Process Verification:

It is the ongoing assurance which is obtained during routine maintenance, continuous verification, and process improvement. It provides assurance that routine production process is in the state of control. It is checked by collecting and supervising information during commercial production.

A successful validation program depends upon information and knowledge from product and process development ¹².

Types of Process Validation

Validation is categorized into different types based on when the validation study is carried out with respect to production, process.

 

They include:

Prospective Validation:

It is carried out prior to the distribution of the product first time produced by the company or if any significant changes are made to manufacture a product which may affect the product characteristics. It involves risk assessment bases of past experience to determine if they might lead to critical situations. It is important for the evaluation of performance characteristics and how the validation is to be carried out ¹⁵. Possible critical situations are identified, the risk is measured and the potential causes are assessed. The trial plans are designed so that it meets all the requirements according to their priorities. These trial runs are then carried out and evaluated, and final judgment is made. If, the results are found satisfactory, the process is selected. Unacceptable processes must be altered and improved until a validation practice demonstrates that the process is satisfactory. This form of validation is important in order to reduce the risk which may occur during production.

 

Concurrent Validation:

This type of validation is carried out during routine production i.e. company will sell the product after their qualification runs¹⁷. This method is effective only if the development stage has resulted in proper understanding of the fundamentals of the process. The first three production-scale batches must be monitored as comprehensively as possible. It involves in-process monitoring of CPP’s and testing of products which helps in generating and documenting that the production process is in a state of control¹⁸. Carrying out this type of validation requires proper justification and authorized approval.

 

Retrospective Validation:

This involves the assessment of previous experience and analysis of historical data of production with the assumption that the composition, procedures, and equipment remain unchanged. This type of validation process is carried out for products which are already in distribution. This is not a quality assurance measure in itself but it should never be applied to new process or products ¹⁹. Batches selected for this type of validation should be representative of all batches produced during the review period, including batches that were unsuccessful to meet the specifications, and should be adequate in number to show process consistency. One of its objective is to support the confidence of the process ¹⁵.

 

Revalidation:

This type of validation is required when there is a change in any of the CPP, formulation, primary packaging components etc. It provides evidence that changes in a process and its environment that are introduced do not adversely affect process characteristics and product quality. Failure to meet process and product specifications also requires revalidation. All the Facilities, systems, equipment and processes, should be periodically accessed to confirm that they remain in valid state. When no significant changes have been made to the validated equipment, facilities, systems etc. an evaluation with evidence that the process meet the prescribed requirements satisfies the need for revalidation.

 

Reasons for Process Validation

Few possible reason of executing process validation activity include introduction of new product or when certain changes are made to existing products, changes in facility, batch size, CPP, change in vendor of API or critical excipient or when there is Out of Specification (OOS) trend among the batches etc. Validation is a method for building and maintaining quality ¹⁶.

 

Merits of Process Validation

ü  Increased and consistent throughput

ü  Decreased rejections and reworks

ü  Reduction in utility costs

ü  Shunning of capital spending

ü  Fewer complaints about process related failures

ü  Scale up can be done more accurately

ü  Rapid and accurate investigations into process deviations

ü  Life and maintenance of equipment’s improved

ü  More rapid automation

ü  Improved employee awareness.

ü  Increased Acceptance

 

Future Prospects

The nature and scope of validation has changed variably over years and is being applied to a variety of situations. It can be said that validation has matured a lot and its future shifts would be minimal. Some of its drivers for the change include advancement in technology, dynamic regulatory environment commercial issues for example automation in identification/inspection will dramatically increase like the use of radio frequency identification bar coding systems will become more prevalent.

 

Robotics is gaining much popularity and is becoming common in many industries which have replaced personnel in repetitive, hazardous and other tasks thereby consistency of results unattainable by humans has been achieved. Process Analytical Technology (PAT) is an approach where there is a use of in situ instrumentation for confirming CQA’s²². PAT is a major advancement in the current practices. A major challenge of today’s industry is to maintain flexibility while being compliant. The use of sophisticated documentation management system is becoming more and more prominent. Contract manufacturing is another facet which is gaining more and more popularity for various and it can be said that it is not a short term trend. The newer facets of validation will continue to emerge and this is certain¹. 

 

CONCLUSION:

Process validation is critical measure in the development of pharmaceuticals. Expertise in these areas can contribute to various significant factors, such as regulatory compliance, greater acceptance of the product in the market ultimately greater profitability. Validation could in fact lead to greater profitability and other benefits^{20, 21}. Experience of the personnel and the whole group performing validation is of major importance because knowledge gained in past helps in development of pharmaceuticals in the right way. A strong mentoring and training program is another prerequisite for successful validation. All the Pharmaceutical companies must therefore maintain very strong and stringent rules so that all its manufactured products are effectively validated so quality safety and hence efficacy of their products is maintained. Ultimately the validation effort reduces the risk to the patient therefore our goal is achieved.    

 

REFERENCES:

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8.        Guidance for Industry: Process Validation General Principles and Practices. U.S. Department of Health and Services. Food and Drug Administration. 2011. 

9.        Guideline on Process Validation, EMA/CHMP/CVMP/ QWP/70278/2012-Rev1. 2012.

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15.     Shein-Chung Chow. Pharmaceutical Validation and Process Controls in Drug Development. Drug Information Journal, 31; 1997: 1195–1201.

16.     Satyabrata Jena et al. Industrial Process Validation of Solid Dosage Forms–An Overview. International Journal of Pharmaceutical Sciences review and research. 4(2); 2010: 145-154.

17.     Nandhakumar et al. An Overview of Pharmaceutical Validation: Quality Assurance View Point. International Journal of Research in Pharmacy and Chemistry. 1(4); 2011: 1003-1014.  

18.     WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty fourth Report, Geneva 1996.

19.      Sharma Chandan et al. Process Validation as an Industrial Practice. International Research Journal of Pharmacy. 4 (2); 2013: 25-28.

20.     Agalloco J. The other side of process validation. J Parenter Sci Technol 40(6); 1986: 251–2.

21.     Agalloco J. Validation- A New Perspective. Compliance Handbook for Pharmaceuticals. Medical Devices and Biologics. New York: Marcel-Dekker, 2004: 83–128.

22.     FDA. Guidance for Industry PAT- Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.

23.     Sarvani V. et al. Process Validation: An Essential Process in Pharmaceutical Industry. International Journal of Medicinal Chemistry and Analysis. 3(2); 2013: 49-52.

 

 

 

 

Received on 19.04.2014          Modified on 22.05.2014

Accepted on 30.05.2014          © RJPT All right reserved