Review Article
Comprehensive Study of Pharmaceutical Process Validation of Solid
Dosage Forms: Quality Assurance Point of View
KOMAL M JADHAV1, JAMEEL AHMED S MULLA2*, RAJENDRA C DOIJAD3,
1Department of Quality Assurance, Shree Santkrupa College of Pharmacy, Ghogaon, Tal- Karad, Dist- Satara, Maharashtra, India
2 Department of Pharmaceutics, Shree Santkrupa College of Pharmacy, Ghogaon, Tal- Karad, Dist- Satara, Maharashtra, India
3 Department of Pharmaceutics, Krishna Institute of Medical Sciences Deemed University’s Krishna Institute of Pharmacy, Karad,
beginning from the process development phase and process control designed to assure that the
and continuing the production phase. Validation drug products have the identity, strength, quality
essentially includes method qualification (the and purity they purport or are represented to
qualification of materials, equipment, system, possess.
building, personnel), however it conjointly
includes the management on the entire method Objective of Process Validation [5]
for continual batches or runs’’. 1. To reduce variation between various
batches.
In 1987, “Process validation is establishing
2. To provide a high degree of assurance of
documented evidence which provides a high
quality of the product.
degree of assurance that a specific process (such
3. To decrease the risk of defect costs and
as the manufacture of pharmaceutical dosage
regulatory noncompliance.
forms) will consistently produce a product
4. To ensure the consistency of the
meeting its predetermined specifications and
manufacturing operation and
quality characteristics”.
reproducibility of the Process.
In 2008, “Process Validation is defined as the 5. To demonstrate the robustness of the
collection and evaluation of data, from the process.
process design stage throughout production,
which establishes scientific evidence that a Advantages of Process Validation [6,7]
process is capable of consistently delivering 1. It is simple process and moisture sensitive
quality products”. and heat sensitive products can also be
In 2011, “The revised guidance also provides processed.
recommendations that reflect some of the goals 2. Expanded real time monitoring and
of FDA’s initiative entities “Pharmaceuticals adjustment of process.
CGMPs for the 21st century – A Risk-Based 3. Decreases the risk of preventing problems
Approach,” particularly with regards to the use and thus assure the smooth running of the
of technological advances in pharmaceutical process.
manufacturing, as well as implementation of 4. Enhanced ability to statistically evaluate
modern risk management and quality tools and process performance and product variables
concepts”. e.g. individuals; mean; range; control limits.
5. Enhanced data and evaluation capabilities
According to EMEA, in March 2012, “Process and increased confidence about process
validation can be defined as documented Reproducibility and product quality.
evidence that the process, operated within 6. Improved ability to set target parameters
established parameters, can perform effectively and control limits for routine production,
and reproducibly to produce a medical product correlating with validation results.
meeting its predetermined specifications and 7. Enhanced reporting capability.
quality attributes.”
Elements of Validation [8]
The Regulatory Basis for Process Validation Design Qualification (DQ): it's documented
[4]
review of the planning, at Associate in nursing
Once the concept of being able to pre-directs applicable stage of stages within the project, for
process performance to meet user requirements agreement to operational and restrictive
evolved, FDA regulatory officials established that expectations.
there was a legal basis of requiring process
validation. The ultimate legal authority is in 1. GMPs and regulatory requirements
section 501(a)(2)(B) of the FD&C Act, which 2. Performance criteria
states that a drug is deemed to bead ultimate 3. Facility air flow, movement flow &
differ the methods used in or the facilities or pressure regimes
controls used for its manufacture, processing, 4. Reliability& efficiency
packing or holding do not conform to or 5. Commissioning requirements
administrated in conformity with CGMP. The 6. Construct ability & installation of
CGMP regulations for finished pharmaceuticals equipment
21CFR 210 and 211 were promulgated to enforce 7. Maintenance& access to critical equipment
the requirements of the act which states that: & instrumentation
There shall be written procedures for production 8. Safety& environment impact
215
Mulla et al / Indian Journal of Novel Drug Delivery 9(4), Oct-Dec, 2017, 214-222
accumulated producing, testing and management Strategy for Validation of Methods [12]
batch information. The validity of a specific method should be
demonstrated in laboratory experiments using
5] Re-Validation samples or standards that are similar to the
A repeat of the process validation to provide an unknown samples analysed in the routine. The
assurance that changes in the preparation and execution ought to follow a
process/equipment introduced in accordance validation protocol ideally written in a very step
with change control procedures do not adversely by step instruction format as follows: Develop a
affect process characteristics and product validation protocol or operating procedure for
quality. the validation.
Process Validation Phases [11] • Define the application purpose and scope
The activities relating to validation studies may of method.
be classified into three: • Define the performance parameters and
acceptance criteria.
Phase1: This is the Pre-validation Qualification • Define validation experiments.
part that covers all activities with reference to • Verify relevant performance characteristics
product research and development, formulation of the instrumentality.
pilot batch studies, scale-up studies, transfer of • choose quality materials, e.g. standards and
technology to business scale batches, reagents;
establishing stability conditions and storage, and • Perform pre-validation experiments;
handling of in-process and finished indefinite • Adjust method parameters and/or
quantity forms, instrumentation qualification, acceptance criteria, if necessary;
installation qualification master production • Perform full internal and external
document, operational qualification and method validation experiments;
capability. • Develop SOPs, for executing the method
routinely;
Phase 2: This is often the method validation • Define criteria for revalidation.
part. It’s designed to verify that everyone • Define sort and frequency of system
established limits of the vital method parameter suitableness tests and/ or analytical
are valid which satisfactory. Merchandise is often internal control (AQC) checks for the
created even underneath the worst conditions. routine; and Document validation
experiments and ends up in the validation
Phase 3: Known as the validation maintenance report.
section, it needs frequent review of all method
connected documents, as well as validation of Industrial Process Evaluation and Selection
audit reports, to assure that there are no for Tablets [13]
changes, deviations failures and modifications to Determine the unit operations needed to
the assembly method which all customary manufacture the tablets.
crepitating procedures (SOPs), as well as
modification management procedures, are 1. Mixing or Blending
followed. At this stage, the validation team Mixing or blending ensures production of
comprising of people representing all major uniform mixture of active pharmaceutical
departments conjointly assures that there are no ingredients and excipients that don't segregate
changes/deviations that ought to have resulted post mixing. Therefore this step is fastidiously
in requalification and revalidation. A careful style scrutinized and valid. Parameters to consider:
and validation of systems and method controls
• Mixing or blending technique
will establish a high degree of confidence that
each one heaps or batches created can meet their • Mixing or blending speed
supposed specifications. It’s assumed that • Mixing or blending time:
throughout producing and management, • Drug uniformity
operations area unit conducted in accordance • Excipient uniformity
with the principle of fine producing follow (GMP) • Equipment capacity/load.
each generally and in specific relevance sterile
product manufacture.
217
Mulla et al / Indian Journal of Novel Drug Delivery 9(4), Oct-Dec, 2017, 214-222
219
Mulla et al / Indian Journal of Novel Drug Delivery 9(4), Oct-Dec, 2017, 214-222
3. Validation reports [16, 17] specifications and needed records. These outline
A written report should be available after procedures, must be followed to claim
completion of the validation. If found acceptable, compliance with GMP principles or other
it ought to be approved and approved (signed statutory rules and regulations. The general
and dated). The report ought to embrace a aspects covered under the SOPs are the
minimum of the following: Title and objective of Preparation and maintenance of work area like
study. washing and sterilization, decontamination and
• Reference to protocol. testing area. Even the work done in the
• Details of material. Equipment. laboratory were documented, for example, the
• Programmes and cycles used. laboratory operations involving the receipt of
• Details of procedures and test methods. reagents, standards, preparation of reagents,
• Results (compared with acceptance labelling and storage, test procedures, reference
criteria). material, identification, handling, storage and use
• Recommendations on the limit and criteria deviations, errors. Even the details of the
to be applied on future basis. equipment sand their maintenance were also
involved [18].
4. SOP (Standard Operating Procedure)
Standard operative Procedures (SOPs) area unit Change Control [19]
issued to specifically instruct staff in areas of Process validation of a solid dosage form should
responsibility, work directions, applicable include an SOP to reassess a process whenever
220
Mulla et al / Indian Journal of Novel Drug Delivery 9(4), Oct-Dec, 2017, 214-222
there are significant changes in the process, Journal of Chemical Environmental and
equipment, facilities, reactants, process Pharmaceutical research, 2010; 3(3): 503-
materials, systems, and so on that may affect the 506.
critical quality attributes and specifications of [7] Himanshu, Pahuja S. A Review on
the solid dosage forms. Such changes should be Pharmaceutical Process Validation.
documented and approved in accordance with International Journal of Pharmacy, 2012;
the scope of the change control SOP. The change 3(7): 56-58.
control SOP should consist of the following [8] Patel Hiren Popatbhai1, Shrivastava AK2,
elements: Jindal Dinesh. Process Validation of
• Documentation that describes the Benazepril HCl 5 mg Tablet. International
procedure, review, approval, and basis for Research Journal of Pharmaceutical and
formal revalidation studies Applied Sciences, 2012; 2(4):1-16.
• Identification of the change and assessment [9] Lakshmana Prabu S, Suriyaprakash TNK,
of its likely implication Ruckmani K, Thirumurugan R Concepts of
• Requirements for monitoring change and Process Validation in Solid Dosage Form
testing needs [Tablet] - An Overview. SAJ Pharma
• Assessment of information and justification Pharmacol 2014
for the change [10] Mohammad Zameeruddin, Kale Shweta S.*,
• Review and formal approval to proceed Jadhav Suryakant B., Kadam Vaishali S.,
Identification of changes made to the Chaware Swapna S. Process Validation Of
physical and chemical composition of the Oral Solid Dosage Form: Tablet – An
solid dosage forms. Overview. World Journal Of Pharmacy And
• Possible regulatory action and customer Pharmaceutical Sciences 2015;4(12): 358-
notification. 373
[11] Sharma Ajay, Saini Seema. Process
REFERENCES Validation of Solid Dosage Form: A Review.
[1] Sharma Sumeet, Singh Gurpreet Process International Journal of Research in
Validation In Pharmaceutical Industry: An Pharmacy andScience2013, 3(2), 12-30
Overview Journal Of Drug Delivery & [12] Neelam Sharma, A. C. Rana, Nimrata Seth.
Therapeutics; 2013, 3(4), 184-188 Process Validation: Impact on
[2] Sharma Chandan, Rana AC, Bala Rajni, Seth Pharmaceutical Industry. An International
Nimrata1An Overview Of Industrial Journal Of Pharmaceutical
Process Validation Of Tablets Journal Of Sciences.2013;4(4):78-92
Drug Delivery & Therapeutics; 2013, 3(3), [13] Rana AC, Bala Rajni, Seth Nimrata, Sharma
175-183 Chandan. An Overview of Industrial
[3] Md. Shoaib Alam, Pharmaceutical Process Process Validation of Tablets. Journal of
Validation: An Overview, J. Adv. Pharm. Drug Delivery & Therapeutics; 2013, 3(3),
Edu. & Res. 2012:; 4:185-200 175-183
[4] Mahesh B. Wazade, Sheel priya R. Walde [14] Annapurna Ojha, Meenakshi Bharkatiya
and Abhay. An Overview of Pharmaceutical and Santosh Kitawat Pharmaceutical
Process Validation and Process Control Process Validation Of Solid Dosage Forms:
Variables of Tablets Manufacturing A Review. World Journal Of Pharmacy And
Processes In Industry. International Pharmaceutical Sciences.2014;3(6):476-
Journal of Pharmaceutical Science and 484.
Research. 2012; Vol. 3(9): 3007-3022. [15] Ch. Sandhya, Brahmaiah Bonthagarala,
[5] Monali Wawre, Babita Dodke, Agrasen Pusuluri Dharani Lakshmi Sai, Konkipudi
Moon and Gajanan Javalkar. Industrial Venkata Sivaiah. Process validation: An
Process Validation in Solid Dosage Form: A essential process in pharmaceutical
Review. World Journal Of Pharmacy And industry. International Journal of Advances
Pharmaceutical Sciences, 2017;6(3):301- in Scientific Research 2015; 1(04): 179-
316. 182.
[6] Kathiresan K, Sreenu VS, Moorthi C, Reddy [16] Good Manufacturing Practices for
B, Kumar B, Reddy M, Yellamula P, Pharmaceutical products, WHO Expert
Manavalan R. Cleaning Validation of Committee on specifications for
Acetaminophen Tablets. International pharmaceutical preparations, 32nd Report,
221
Mulla et al / Indian Journal of Novel Drug Delivery 9(4), Oct-Dec, 2017, 214-222
222