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Also, cGMP section § 601.12 requires validation for changes to an approved application.
“Before distributing a product made using a change, an applicant shall demonstrate through
appropriate validation… the lack of adverse effect of the change on the identity, strength,
quality, purity, or potency of the product….”. This requirement governs changes in “…
product, production process, quality controls, equipment, facilities, responsible personnel, or
labeling….” Whether the change is major or minor, a VMP will provide the Agency the
basic components of the organizational validation philosophy and intentions to comply with
applicable regulations.
For Medical Devices, 21 CFR 820 serves as the cGMP requirements section. Section 820.75
deals with Process Validation and states that the “validation activities and results, … and
where appropriate the major equipment validated, shall be documented.” This outlines the
need for a validation program, and the VMP can help comply with this requirement by
documenting which major equipment systems will be validated.
All regulated industries are struggling to understand and comply with the requirements of
21CFR 11, which addresses Electronic Records and Electronic Signatures, and requires
“Validation of systems to ensure accuracy, reliability, consistent intended performance, and
the ability to discern invalid or altered records.” Based on the number and complexity of the
computer systems utilized, a separate Computer System Validation Master Plan may need to
be written and referenced in the VMP. Here again, this can serve as a vehicle for a preexecution meeting with the FDA in order to gain guidance. These specific instances do not
explicitly detail the requirement for a Validation Master Plan; however, a properly crafted
VMP will document the pathway to compliance.
Increasingly, the FDA is showing it agrees. Recently, the Agency issued a “Guidance for
Industry” document, meant to reflect the Agency’s current thinking, which explicitly calls
out for a VMP. In “Guidance on Quality System Regulation Information for Various
PreMarket Submissions,” a requirement of the Quality System Manufacturing Dossier is “a
copy of the Validation Master Plan or a description of which manufacturing processes have
been or will be validated. A Validation Master Plan is a convenient method of quality
planning for process validations required in the manufacturing of the device (§ 820.20(d)).”
Clearly the expectation of the Agency is that organizations have a validation strategy as part
of product and process development, and translate that strategy into a plan that will lead to
an installation compliant with regulatory requirements.
Manufacturing Process Model
Recently it has been observed that the pharmaceutical industries have been actively involved
in searching advanced manufacturing processes. These can help in reduction of the
manufacturing costs and improve the quality of the product. One of the most capable ways is
changing from batch to continuous pharmaceutical manufacturing processes. The continuous
method of production means enabling a steady- state operation. The quality of product
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shows only low inconsistency over time. Thus, a well-designed continuous product
manufacturing process can produce improved quality of product and uniformity.
Moreover, a batch process usually requires more steps than continuous product
manufacturing process. It also helps in reduction of capital and operation costs. This results
in better economic efficiency. The continuous product manufacturing process could be
successfully implemented if the properties of materials and conditions for operations can
jointly affect the process behavior and features of the product.
Process modeling can help this step and be used to store this knowledge. To pharmaceutical
manufacturing processes if the modeling technique is applied, a better understanding of the
process can be achieved by conducting a limited number of experiments. The process
dynamics can be better understood by utilizing a well developed and validated process
model.
Process modeling
Modeling of the solids-based pharmaceutical processes is difficult mainly due to the
complexity of the particle-level and bulk behavior of flows of material. The Discrete
Element Method (DEM) policy has been used for modeling various pharmaceutical
processes. If the motion and positions of each particle is followed individually by the
Discrete Element Method (DEM), a huge amount of detailed information of the dynamics of
particles can be obtained. This information is usually difficult to be obtained directly from
physical experiments, but can be crucial to the investigation of particle level phenomena
such as segregation, agglomeration. However, the DEM simulations are computationally
intensive and can only be applied to the systems with a limited number of discrete particles.
The Population Balance Models (PBMs) explain the time-dependent properties for a group
of entities. A set of partial differential equations involving the mass, momentum, and energy
balance for the systems of interest are used.
The term ’entities’ are referred to particles whose states are described by a vector containing
both internal coordinates (such as particle size, mass) and external coordinates (e.g., physical
locations). Recently, hybrid models combining DEM simulations and PBMs have been
developed to describe pharmaceutical processes such as granulation, milling, and mixing.
A broad range of modeling techniques can be categorized as a data-drive approach.
Response Surface Methodology (RSM), probably the mostly used regression technique,
describes the process with a low-degree polynomial model. A RSM model is usually
constructed based on physical experiments using a Design of Experiment (DoE) sampling
plan. Partial Least Squares (PLS) regression is a multivariate regression approach which
projects the dataset to a lower dimensional latent space. Two raw materials, active
pharmaceutical ingredient (API) and excipient are fed to a co-mill for the purpose of delumping, after which the mixtures together with a lubricant, are transferred to a blender for
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mixing. The blends are sent to the press where tablets are continuously produced. It can be
noticed that as the feeder runs, refilling of the materials is required, which can cause
temporal variations to the flow rate. In the bottom two charts, the propagation of such
variations after the blender is predicted. It can be observed that after mixing the variations in
the API composition are dampened to a much smaller level. Such predictions are useful in
choosing the best refilling strategy that leads to products with desired quality attributes.
URS (United Registrar of System)
In 1994 the URS has been established. It is an International organization with headquarter in
the UK. It is a recognized body to audit the risk management, governance
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, training,
climate change validation and verification energy audits and social compliance audits.
A group of dynamic professionals well acquainted with state-of-art technology in
certification, inspection and training has started the URS. The organization is headed by Mr.
David Riggs who has entrepreneurial adeptness and sharp acumen. The URS has various
offices around the world, served many organizations and finally made it a global leader in
assessment and certification field. Since beginning the organization has been in line with the
European culture and its objectives have been inclined towards the expectations of the
clients across the world.
In early 2001, under the leadership of Sri Mukesh Singhal the operation of the URS has set
up. Sri Singhal has professional competency. Through his cooperation a joint venture with
URS (UK) was formed and he remains the instrumental in transforming Mr. Rigg’s vision
into reality. Mr. Singhal is now Dy. Managing Director of URS Global.
Presently URS is a member of URS Holdings and is operating worldwide through a series
and network of offices. At present, the organization runs offices present in 44 world hubs
and regional offices in more than 44 countries and with more than thousands certified
locations. The company certifies business ranging from global brands to small, locally
owned businesses. Credibility, Confidence, Commitment and Competition or popularly
known as the 4C are the principle of the company’s growth and business.
Credibility: It is an independent certification body and acts in accordance with the principles
governing the conduct of each business.
Confidence: As a group URS conducts accreditation and recognitions by internationally
reputed boards such as the UKAS, NABCB, IATF and many more. Throughout the world
the group companies follow a uniform management system and maintain accreditations as
individual legal entities providing recognition through the multi-lateral agreement (MLA)
across the countries.
Commitment: The company, URS has been established just about three decades before by
senior experienced managers around the world. It inspects and certifies just like family
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business. The company is dedicated to assist its clients in their needs to ensure their success.
URS believes that partnership and practicality are very much important in today’s business
relationships.
Competitiveness: URS realizes the efficiency of services and backs it up with competitive
pricing as compared to the current commercial scenario. URS invests much in IT solutions
and staff training. Value added services are essential and thus, URS provides its best possible
services to its clients, for this purpose the URS has made partnership with the URS Academy
Business to provide essential business services so that a significant competitive edge can be
maintained.
The International Accreditation Forum (IAF) is the world’s association of Conformity
Assessment Accreditation Bodies and other bodies who are interested in conformity
assessment in the fields of management systems, product, and services, personal and other
similar programmes of conformity assessment. The accreditations held by URS are all
performed by Accreditation Bodies that are members of the IAF.
Various Accreditation Bodies
UKAS (United Kingdom Accreditation Services) recognizes URS Certification of the
management system to such standards as ISO 9001, 14001, 45001, 20000, 27001,
22000, 13485 and others. The appointed legal entity is United Registrar of Systems
Ltd., United House, 4 Hinton Road, Bournemouth, United Kingdom.
IATF (International Automotive Task Force) has approved URS as an accredited body
for certification in the automotive industry according to ISO/TS 16949 – IATF 16949
standards. The appointed legal entity is the United Registrar of System Ltd.
NABCB (The National Accreditation Board for Certification Bodies) is the Indian
accreditation body. URS Holdings selected the NABCB for its growing importance in
the Asian market and particularly in India. The appointed legal entity is URS
Certification Ltd., F-3, Sector 6, Noida, NCR- Delhi, India.
DAC (The Dubai Accreditation Centre) is an accreditation agency for Dubai. URS
Holdings selected DAC for accreditation as the Government of Dubai has made it a
requirement for all companies that prepare or produce food to be certified for HACCP
scheme or ISO 22000. The appointed legal entity is URS ME FZC, P. O. Box 7871,
SAIF Zone, Sharjah, United Arab Emirates.
EGAC (Egyptian Accreditation Council) is an accreditation body in Egypt selected by
URS Holdings for its growing importance in Egyptian market. The appointed legal
entity is URS Egypt, United Registrar of Systems Egypt Ltd., 37 EI Hagaz EL
Mohndseen, Giza, Egypt, Postal Code 12655, regarding the EGAC schemes and
accreditations.
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SAC (Singapore Accreditation Council) is an accreditation body in Singapore selected
by URS Holdings for its growing importance on the Singapore market. The appointed
legal entity is URS Far East Pte Ltd., 7500A Beach Road #06-323. The Plaza,
Singapore, regarding the SAC schemes and accreditations.
DAKKS (Deutsche Akkreditierungsstelle) is an accreditation body in Germany which
approves URS Certification as an accredited subject for ISO 50001 Energy
Management and ISO 28000 Security Management System for the Supply Chain. The
appointed legal entity for ISO 50001 and ISO 28000 standard is United Registrar
Systems GmbH, Freiberger Str. 39, 01067 Dresden, Germany, regarding the DAKKS
systems accreditation.
TAF (The Taiwan Accreditation Foundation) is the only body in Taiwan recognized by
Government for the accreditation of conformity assessment against international
standards. The URS Holdings selected TAF for accreditation as the BSMI of Taiwan
has made it a requirement for all companies if their products want to be certified for
the CNS Mark or Regulatory Product Inspection. The appointed legal entity is URS
Taiwan Ltd., 7F – 9, No. 20, Ln. 609, Sec. 5, Chongxin Rd., Sanchong Dist., New
Taipei City 241, Taiwan (R.O.C.), regarding the TAF schemes and accreditations.
CAI (Czech Accreditation Institute) is an accreditation body in Czech Republic, which
approves URS as an accredited subject for the ISO 9001 Quality Management System,
ISO 14001 Environmental Management System, ISO 27001 Information Security
Management System, ISO 45001 Health and Safety Management System, ISO 50001
Energy Management System. The appointed legal entity for accredited standards
under CAI is United Registrar of Systems Czech, S.R.O., Rybna 678/9, 110 00 Praha
1, Czech Republic.
URS conducts independent technical quality inspections and advance the process
because these are very important to reduce the risk in the supply chain. These reduce
the costs and potential delays; improve the quality and safety of products that meet
customer requirements, local as well as international standards.
Technical Quality inspections by URS:
Independent inspection at suppliers’ premises on behalf of the client, Observing all
the technological processes such as: NDT, stress tests, functional tests, heat treatment,
coatings, etc.
Continuous control of quality in accordance with the manufacturer's inspection and
test plan (ITP).
Verifying the measurement and instrumentation equipment used by the manufacturer.
Examination of the qualifications of the manufacturer's testing staff. Evaluation of
test results.
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Controlling the quality in accordance with the international or local standards.
Inspection of the product that affect the quality e.g.: quantity, dimensions, accuracy.
Performing the document control (manufacturer’s final documentation).
Inspection of packaging and labeling of the product.
Inspection during loading or unloading.
It accelerates:
Supervision of the processes at manufacturing premises to verify the capacity and
organizational level required to meet the customer's contract.
Comparison of the manufacturer's schedule with the current order status.
Control of subcontracting.
Regular reviewing of the order status and its progress.
The purposes of URS Inspection
Management of risks, increase of profits and meeting the commitments: through
individual or integrated solutions for each aspect of the supply chain.
Minimizing the risks during production and thus, increasing its safety and quality.
Ensuring that the products being manufactured and supplied are as per the standards
and specifications provided.
Observation of delivery dates:
Compliance with the complex legislative requirements: including standards and regulations
at national and international level relating to the production and sale of goods.
To ensure that the delivery of products in the same condition as found at the time of loading,
and the unloading including the control of the same safety in accordance with the control
documents.
Design Qualification (DQ) of facilities
The Standard Operating Procedure should be attached to this generic design qualification
protocol. Safety and security along with the operability of the users are to be included in
detail. The document will lead through all these design aspects that allows deleting some
points which are not important or relevant to the equipment. It is a document easy to use and
ensures that the design qualifications are relevant, up to date and easy to execute. Generally,
all these requirements are given in a tabular form. This allows fast and clearly presented
results to be obtained.
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The design qualification is the first element of validation of new facilities, systems or
equipment.
It is necessary to demonstrate and document the compliance of the design with GMP.
Installation qualification (IQ) of facilities
Installation qualification is a method of demonstrating and documenting (establishing) with
confidence that all major processing, packaging equipment and ancillary systems are
conforming the installation specifications, equipment manuals, schematics, and engineering
drawings. At this stage of validation, the examination of equipment design, determination of
calibration, maintenance and adjustment requirements are also done. On new or modified
facilities, systems, and equipment installation qualification (IQ) should be performed.
Installation Qualification should include, but not be limited to the following:
Installation of equipment, piping, services, and instrumentation should be checked to
current engineering drawings and specifications.
Collection and collation of supplier operating and working on instructions and
fulfilling maintenance requirements
Calibration requirements
Verification of materials of construction
Description of equipment, piping, and Instrument diagrams
Principle of operation
Specifications of functional facility
Design requirements
Equipment utility requirements, equipment specification, equipment features
Operational Qualification (OQ) of facilities
The Operational qualification (OQ) should be conducted by using an authorized protocol.
The critical operating parameters for the equipment and systems should be identified at the
operational qualification stage. The plans for the operational qualification should identify the
studies to be undertaken on the critical variables, the sequence of those studies and the
measuring equipment to be used and the acceptance criteria to be met. Studies on the critical
variables should include a condition or a set of conditions including upper and lower
processing and operating limits called as “worst-case” conditions. The OQ completed
successfully should allow the finalization of operating procedures and operator instructions
documentation for the equipment. This information would be used as the basis for training of
operators in the requirements for satisfactory operation of the equipment.
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Once IQ and OQ are completed successfully, the equipment can be released for the next
stage in the process validation. This works till calibration, cleaning, preventive maintenance,
and operator training requirements have not been completed and documented.
Operational qualification (OQ) should follow installation qualification (IQ). Operational
qualification (OQ) should include, but not limited to the following:
Verification that all loop installations,
Insertion of a brief description of that part of the validated process for a product,
Insertion of a brief description of the operational function,
An integrated loop test verification,
Testing of alarms,
Testing of interlocks and tolerant conditions,
Testing of database or data storage integrity,
Testing of report generation and event history,
Verification of the functionality of the equipment,
Challenge of software where required,
Review of functions of the system to verify compliance with 21CFR Part 11,
Verification of the system, if the system is a 21CFR Part 11,
To prevent Electromagnetic interference and compatibility
Performance Qualification (PQ) of facilities
Performance qualification (PQ) should pursue successful completion of Installation
qualification and Operational qualification. PQ should include, but not be limited to the
following:
Tests, using production materials, qualified substitutes or simulated product that has
been developed from knowledge of the process and the facilities, systems or
equipment.
Tests to include a condition or set of conditions encompassing upper and lower
operating limits. Although PQ is described as a separate activity, it may in some cases
be appropriate to perform it in conjunction with OQ.
Qualification of established (in-use) facilities, systems, and equipment.
References
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