Draft Policy on Quality System as an Integrated Policy

PTPS-DP-10-2014
Quality System as an
Integrated Policy for Safe
Drugs & GMP Compliance
Current Good Manufacturing Practice
Regulation & its Compliance via
Systematically Designed Approach
consistent to Modern Regulatory Age
Roohi Bano Obaid, Deputy Drugs Controller,
Drugs Regulatory Authority of Pakistan
For Policy, Training and Pharmacy Services
February 2014

Drafted by Roohi Bano Obaid, Deputy Drugs Controller, DRAP for Policy, Training & Pharmacy Services, February 10th 2014 Page 2 of 16
Quality System
as an Integrated Policy
Disclaimer
In between pre-marketing evaluation and post-marketing surveillance, compliance and
monitoring of compliance of current Good Manufacturing Practices (cGMP) are a continuous
challenge to ensure safety, efficacy, strength, identity, purity and quality of drugs. To generate
information, its trending in terms of data and to convert it into a meaningful signal, a science
based systematic approach is indispensible for earlier as well as to walk within the age of
globalization and harmonization. Referring guidance of United States-Food and Drug
Administration (US-FDA) as a main source and focusing on the knowledge gained with the
philosophy of learn, unlearn and relearn, a policy document is drafted and presented for
comment(s) along reference or personal suggestion without reference.
1. INTRODUCTION AND BACKGROUND:
Subsequent to both in general consultative meetings among stakeholders and specifically in
between Manufacturers and Regulators, GMP regulations were published in May 1998 in
Pakistan. There has been much advancement in manufacturing sciences and growing importance
in current thinking and understanding of quality systems. The purpose of this policy document is
to provide guidance and extend help to manufacturers in understanding and implementing the
modern science based quality systems and risk management approaches. It will bring dynamic
changes and prove as a tool to superimpose the requirements of the current good manufacturing
practices (cGMPs) regulations consistent and harmonized with the ongoing modernization,
globalization and harmonization initiatives of the world. It is tried best to describe a
comprehensive quality systems (QS) model, stressing the importance and consistency of the
model with the cGMP regulatory expectations for manufacturing drug products in a simple and
clear language and an effective manner.
Although GMP regulations are clear in understanding but document will focus and help to
exhibit how and where the elements of this comprehensive model can fit within it. The space
available within science and inherent flexibility of the cGMP regulations should enable
manufacturers to implement a quality system in a form that is appropriate for their specific
operations. The paradigm shift both in the practice of regulations as well as pharmaceutical
practices from reactive approach to proactive approach emphasize to build the quality into the
product instead of relying on testing.

Quality System
This policy document is intended to incorporate current innovations and challenges in 1998
cGMP regulations to ensure alignment of thinking process within the manner of regulatory
science. Several factors contribute the need for issuance of this policy document as follows:
i. Availability of safe and quality drug to the patient is the shared responsibility of the
Drugs Regulatory Authority of Pakistan (DRAP) and manufacturers. Desired consistency
among doses in terms of therapeutic drug reaching to the body, contamination and cross-
contamination within the acceptable limits, integrity of drug throughout the process and
tracing the track to reach the footsteps of history is a challenge and need to be efficiently
addressed up to the level of common sense and brackets of science.
ii. This policy document will highlight common elements between the cGMP regulations
and Quality Management Systems and subsequently be helpful for both DRAP and
Manufacturers to understand the expectations of DRAP and to resolve the disputes on the
merit. The potential of variability among the DRAP regulated products will be reducing
and within the expected regulatory limits under this policy document.
iii. Innovations and changes (Technological Advancement) are regulatory challenges and to
maintain desired quality both DRAP and manufacturers needs effective control in
manufacturing process and product knowledge with the use of effective risk management
practices. This policy document will be helpful to decrease the regulatory burden and
classification of degree of regulatory oversight associated thereof.
iv. This policy document will provide the necessary outline, required for designing of quality
from the development of product and throughout its life cycle. Nature and complexity of
a product and its manufacturing process may be adjusted within the pre-defined qualified
space available to meet acceptable standards of quality.
2. SCOPE OF THE POLICY DOCUMENT:
This policy document applies to manufacturers of human drug (pharmaceutical/ biological)
products (APIs and finished pharmaceuticals). It may equally be good for veterinary and other
healthcare products if quality is a prime concern.

Quality System
3. QUALITY SYSTEMS & CGMP REGULATIONS:
Background key concepts to describe quality systems for manufacturing of drug products are
emphasized to simplify the need of policy.
3.1 Quality:
Predefined and approved (1) identity, (2) strength, (3) purity, and other (4) quality attributes of a
DRAP’s authorized drug product are required to ensure the label claims in terms of its efficacy
and safety.
3.2 Designing of Quality during Pharmaceutical Development:
Robustness to attain consistency in predefined quality attributes is an ultimate goal of
pharmaceutical development. Scientific understanding and behavior of product and process to
control the variability and to sustain the shocks within the available space and up to the extent of
its scale up are the only tools to address possible challenges beforehand under the proactive
approach. The available cGMP regulations are flexible enough to incorporate the said concept.
3.3 Risk based Approach in Managing the Quality:
Identification and assessment of risk to produce harm is an important arm to define pathways of
an efficient and effective quality system. This management of quality within the scale of risk will
be helpful in establishment of specifications and process parameters for drug manufacturing,
assessment, management and mitigation of the risk associated with change in process or
specifications. It will also favor to determine the degree of deviations and navigation of
appropriate actions.
3.4 Out of Specification (OOS) and Out of Trend (OOT):
If anything goes outside the circle of established specifications during the manufacturing or
reviewing, is not always substandard but out of specifications. All drug product production and
control records need to be reviewed and approved to determine compliance with all established,
approved written procedures before a batch of a drug product is allowed to be consumed. Any
signal although it is within the circle but growing towards the scale of uncertainty is an out of
trend and may lead to the possibility of failures.

Quality System
3.5 Root Cause Analysis:
Any unexplained discrepancy or the failure of a batch or any of its components to meet any of its
specifications need to be thoroughly investigated. The investigation should extend to other
batches of the same drug product and other drug products that may have been associated with the
specific failure or discrepancy.
3.6 CAPA (Corrective and Preventive Action):
Every investigation triggered by out of specification or out of trend result or incidence etc. leads
to assigning of root cause(s), which subsequently demands for corrective action and measures to
avoid recurrence of such trigger thereof. Written record of such investigation should include the
conclusions and follow-up.
3.7 Change Control:
Changes that alter specifications, a critical product attribute or bioavailability or require to be
assessed for its safety especially in the case of Biologicals are subject to submission and prior
regulatory approval. The change control monitors all types of changes which can influence the
process or product quality and states the measures necessary for implementing the change or
decides that a change should not be implemented. Change control and management within and in
line with the regulation helps to prevent unintended consequences in terms of the spirit of
compliance of GMP. With the binding of appropriate change control mechanism manufacturer
can justify the change is covered within the space of its design outline during the product
development. This process not only controls the variability but keeps improvement up with the
help of assessment of real time knowledge gained during the product life cycle.
3.8 Periodic Product Review for Quality:
Regular periodic reviews for quality of drug products are the tool to get insight of product and
process compliance with standards and specifications. This snapshot exercise verifies the
consistency of the current process in place, the appropriateness of current specifications for
materials (both starting/raw and processed) and end product to bring to light any trends, and to
capture signals to improve the process and finally product from any uncertainty. Such science

Quality System
based continuous periodical product review process for quality need to be conducted at
appropriate intervals but not more than a year.
Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms,
sterile products, etc. where scientifically justified. The evaluation of review outcome demands
any corrective or preventive actions or revalidation by default and effectiveness of review need
to be monitored and measured.
3.9 Supplier (Vendor) Qualification:
Consistent supply of approved quality of material whether it is an excipient, active
pharmaceutical ingredient, packaging material for the case of product or accessories for the case
of services, process, machineries etc. is one of the integral constituent of quality. To build the
quality and maintain the trust, qualification of the supplier need to be conducted on regular basis
via comprehensive supplier qualification program and challenged accordingly, when required.
3.10 Instrument Calibration:
Process to build the confidence with high precision and accuracy etc. of measuring instruments
revolving around the manufacturing, and determination of quality of product; need to be reliable
up to the level of required scientific expectations for the particular segment of its function. Due
to complexity among the instruments, their use in measurements during the manufacturing
process and plenty of integrated and inter-related functioning, a well defined Master Calibration
Plan (MCP) need to be in place to avoid any cross collision in dispensing of intended operations.
This plan helps to keep instrument free for its calibration upon due time etc. Effective
documentation and traceability of record of all activities within reasonable retrieval time is also
the integral part towards the journey of quality.
3.11 Qualification and Validation:
Consistent working with equal response/action and voice among the personnel, learn, unlearn
and relearn are one of the indispensible approaches with the improvement of technology and
process etc. To get the instrument reliable and process capable to demonstrate and reproduce the
results within the pre-defined degree of acceptable variation, validation and re-validation

Quality System
exercise is necessary in due course of time and required due to any good reason. A well defined
Master Training Plan (MTP) for personnel and Master Validation Plan (MVP) are also required
in line with MCP to commensurate with Qualification and Validation to make the exercise
successful.
3.12 Facility/Instrument Maintenance Plan:
To maintain facility within its intended design, to maintain consistency in quality of drug
products and any possible malfunctioning of already validated equipment requires periodical
preventive maintenance and corrective maintenance in case of any good reason. Likewise, a well
defined Master Maintenance Plan (MMP) is required to be in place.
3.13 Complaint Handling:
Importance to feedback and complaint is one of the fundamental features to uphold and improve
quality. For the purpose an effective and efficient qualified procedure requires to be in place
within reasonable response time and classified level of actions to ensure the best for safety of
public and quality of drugs.
3.14 Recall/Returned Goods:
To acknowledge the shared responsibility of safety of public, a voluntary qualified recall
procedure with different degree of actions is required to be in place to combat the situation in an
efficient and effective manner for recalled and returned goods.
3.15 The Quality Operations:
All measures triggered, controlled and ensured to achieve the quality attributes of product within
the compliance level, practice within approved working range and facility /utility services in line
with its intended design are executed by the Quality Operations (QO). QO pays attention and is
bound to ensure regulatory compliance via known defined and authorized procedures. The
oversight of total operations including quality control, production, engineering, utility services,
supplier qualification etc. alone or in a multidisciplinary team approach is the prime
responsibility of QO. The concept of QO is also consistent with modern quality systems in

Quality System
ensuring that the various operations associated with all systems of manufacturing facility are
appropriately planned, approved, conducted, and monitored.
The essence of cGMP demands that QO should have the authority to create, monitor, and
implement a quality system. However, this authority does not substitute for, or exclude, the
regular responsibility of other personnel involved in manufacturing of drugs to perform their
duties designed to build quality into a drug product. Likewise, the QO should not take additional
responsibilities of other units of a manufacturer’s organization, such as the responsibilities
handled by production department including engineering, utility services and development work
etc. Since, manufacturing of quality product is the responsibility of the manufacturer, therefore,
all personnel involved in entire manufacturing process and the QO are critical and very much
important. The other important responsibilities of QO but not limited to, are described below
which are consistent with modern quality system approaches:
• Implementation and satisfactorily completion of controls defined for manufacturing process
of the drug product.
• Determination of appropriateness of procedures and specifications for manufacturing of a
particular product and its implementation.
3.16 Six-system Inspection Model:
US-FDA inspection model widely used around the world which is based on five different
integrated systems of a manufacturing facility enlisted below engraved with one independent
quality system provides the foundation for the interlinked functions within it. Such systematic
approach gives swift access to monitor the state of control of each system.
i. Quality System
This system assures overall compliance with cGMPs and internal procedures and
specifications. The system includes the quality control unit and all of its review and
approval duties (e.g., well-defined change control, reprocessing, batch release, Periodic
Product review for Quality, validation protocols, and reports, etc.). It includes all product
defect evaluations and evaluation of returned and salvaged (products exposed with
unclassified situations of nature such as storm, flood etc.) drug products.

Quality System
ii. Facilities and Equipment System
This system includes the measures and activities which provide an appropriate physical
environment and resources used in the production of the drugs or drug products. It
includes:
a) Buildings and facilities along with maintenance;
b) Equipment qualifications (installation and operation); equipment calibration and
preventative maintenance; and cleaning and validation of cleaning processes as
appropriate. Process performance qualification will be evaluated as part of the inspection
of the overall process validation which is done within the system where the process is
employed; and,
c) Utilities that are not intended to be incorporated into the product such as HVAC,
compressed gases, steam and water systems.
iii. Materials System
It relates to activities carried out to control finished products, their components, including
water or gases that are incorporated into the product, containers and closures. It includes
validation of computerized inventory control processes, drug storage, distribution
controls, and records.
iv. Production System
This system includes measures and activities to control the manufacture of drugs and
drug products including batch compounding, dosage form production, in-process
sampling and testing, and process validation. It also includes establishing, following, and
documenting performance of approved manufacturing procedures.
v. Packaging and Labeling System
This system includes measures and activities that control the packaging and labeling of
drugs and drug products. It includes written procedures, label examination and usage,

Quality System
label storage and issuance, packaging and labeling operations controls, and validation of
these operations.
vi. Laboratory Control System
It includes measures and activities related to laboratory procedures, testing, analytical
methods development and validation or verification, and the stability program.
4. THE QUALITY SYSTEMS MODEL:
This policy document refers to US-FDA Quality Systems model on robust quality system to
achieve a state of control enabling production of a consistent and acceptable quality drug
product. It outlines following four major factors for further elaboration and elucidation
accordingly.
4.1 Management Responsibilities
4.1.1 Establishment of Quality System (QS) is the responsibility of the firm’s top
management. The management should provide leadership for the successful
functioning of the QS. The planning and ultimately the working of the QS should be
line with the manufacturer’s strategic plans to ensure that the system is part of the
manufacturer’s mission and quality strategies.
4.1.2 The Responsibilities and Authorities of all individuals within the organization
structure should be designed and documented as such to ensure the production and
supply of quality products. An organization is responsible to authorize the individual
appointed to lead the QS, to detect problems and implement solutions. The
organization should receive prompt feedback on quality issues.
4.1.3 The Design and Implementation of QS should provide clear organizational
guidance and facilitate systematic evaluation of issues. Control procedures should be
established and documented to complete, secure, protect and archive records,
including data which provide evidence of operational and quality system activities.
Policies, objectives and plans under the umbrella of modern QS are the basic tools
which enable the senior managers to keep track of their vision of and commitment to

Quality System
quality at all levels of the organization. A strong commitment to quality should be
incorporated into the organizational mission by the senior management. Furthermore,
an organizational quality policy should be developed in line with this mission,
committing to meet the requirements and improving the QS and propose objectives
for the fulfillment of the quality policy. It should be communicated to and understood
by the personnel in the organization. The QS approach requires quality planning for
identification and allocation of resources and application of methods to achieve
quality objectives. The QS plans should be documented and effectively
communicated to concerned personnel to ensure awareness of how operational
activities are aligned with strategic and quality goals.
4.1.4 The system should be reviewed
 The appropriateness of quality policy and objectives
to keep abreast of its continued suitability,
adequacy and effectiveness. Following aspects, but not limited to, should at least be a
part of review:
 The results of audits and their assessments
 Customer feedback including complaints
 The analysis of data trending results
 The status of actions to prevent a potential problem or a recurrence
 Any follow-up actions from previous management reviews
 Any changes in business practices or environment that may affect the quality
system (such as the volume or type of operations)
 Product characteristics meeting the customer’s needs
4.15. The review should be more frequent during the development and
implementation of new QS comparable to that when the QS have matured
 Improvements to the quality system and related quality processes
. Review
outcomes generally include:
 Improvements to manufacturing processes and products
 Realignment of resources

Quality System
4.1.6 The QS requires that the results of a management review should be recorded.
The planned actions should be implemented using effective corrective and preventive
action and change control procedures.
4.2 Resources
4.2.1. Establishment of robust QS and compliance of GMP regulations requires the
foundation of appropriately allocated resources
 To supply and maintain the appropriate facilities and equipment to
consistently manufacture a quality product.
. There must be sufficient resources
for the QS and operational activities which mainly include the following:
 To acquire and receive materials that are suitable for their intended purpose.
 For processing the materials to produce the finished drug product.
 For laboratory analysis of the finished drug product, including collection,
storage, and examination of in-process, stability, and reserve samples.
4.2.2 The QS approach calls for continued training to ensure the employees stay
proficient in their operational activities and understanding of GMP regulations. The
training should address the policies, processes, procedures and written instructions
related to the operational activities, the product/service, the QS and the desired work
culture (like team building, communication, change, behavior). It is imperative that
the personnel should understand the impact of their activities on the product and the
customer.
4.2.3 The management should create and support a problem-solving and
communicative environment within the whole organization. Cross-functional groups
may be developed for ideas sharing and ultimately for the improvement of procedures
and processes.
4.2.4 The QS also requires that contract agreement with any party providing any
service must be clearly defined in black and white describing the materials or service,
quality specification responsibilities, and communication mechanisms. The contract
firm should be qualified prior to signing of contract with that firm. The contract

Quality System
firm’s personnel should be adequately trained and monitored for performance
according to their QS. It is worthy to note that the contract firm's and contracting
manufacturer’s quality standards should not conflict. Moreover, the management of
the contractor should be familiar with the specific requirements of the contract.
4.3 Manufacturing Operations
4.3.1 The QS approach requires the building up of quality from the design to delivery.
Controls should be in place over all changes. The documentation of manufacturing
process and procedures, associated controls including changes to them if any, should
be capable enough to identify and track the sources of variability.
4.3.2 Modern QS approach requires ensuring that all inputs to the manufacturing
process are reliable. To achieve this purpose, analysis of data trends for acceptance
and rejection of materials should be an essential element of purchasing controls to
monitor supplier performance. The QS approach also requires periodic auditing of
suppliers based on risk assessment. An audit should include the systematic
examination of suppliers QS to ensure reliability in addition to observation of
testing/examination conducted by the supplier for determining the reliability of its
Certificate of Analysis (COA). Procedures should be established to verify that
materials are from qualified sources. Procedures should also be in place to cover the
acceptance, use or rejection and disposition of materials produced by the facility. E.g.
purified water. Systems for such production should be designed, maintained, qualified
and validated to ensure the materials meet their acceptance criteria.
4.3.3 In modern QS, a design concept established during the product development
matures into a commercial design after process experimentation and progressive
modification. Risk based approach can facilitate to identify areas of weakness or
increased risk and factors influencing Critical Quality Attributes (CQA) that should
be taken into account more vigilantly. Scale up studies should be used to lend a hand
to demonstrate that a fundamentally sound design has been completely developed.
Thus, a sufficiently robust manufacturing process should be ready before commercial
production. Conformance batches provide initial proof that design of the process
produces the intended product quality. Nevertheless, primary commercial batches can

Quality System
provide evidence to support the validity and consistency of the process, the entire
product life cycle should be concentrated on by the establishment of continual
improvement mechanisms in the QS. Hence, process validation is not a one-time
affair, but an activity that continues throughout the product’s life.
4.3.4 As commercial production progresses, the records from production provide
insight into a product’s state of control. Such records determine the need for process
improvement or change in the process. In QS, a manufacturer has to develop
procedures that monitor, measure, and analyze the operations including analytical
methods and /or statistical techniques. Monitoring of the process is important due to
the limitations of testing. To maintain quality, prior to completion of manufacturing,
the manufacturer should take into account the storage and shipment requirements to
meet special handling needs.
4.3.5 The QS requires that trends should be continually identified and evaluated. The
resultant information can be used for continuous quality monitoring, identification of
potential variances, strengthen the data collected for periodic product review, and
facilitate improvement throughout the product lifecycle.
4.3.6 An integral part of the QS is handling non-conformities and /or deviations
• Correct the non-conformity
.
Discrepancies may be detected during any stage of the process or during quality
control activities. All discrepancies do not lead to product defects, however, its
documentation and appropriate handling is essential. If the discrepancy leads to affect
a product quality, the investigation process is critical. QS calls for identifying the
responsible person for halting and resuming operations, recording non-conformities,
investigating discrepancies and taking remedial actions. A product or process not
meeting the requirements should be identified and segregated to avoid distribution to
the consumer. Remedial action as appropriate should follow such as:
• With proper authorization, allow the product to proceed with justification of
the conclusion regarding the problem’s impact.
• Use the product for another application where the deficiency does not affect
the product’s quality.

Quality System
• Reject the product.
If a product not meeting the requirements has been released, it should be recalled.
4.4 Evaluation Activities
The QS requires that systematic evaluation be carried out to monitor the working of
the ongoing system. It can be achieved by following activities:
4.4.1Trend Monitoring: Continuous monitoring of trends and improving systems
can be achieved by monitoring data and information, identifying and resolving
problems, and anticipating and preventing problems. Procedures involve collecting
data from monitoring, measurement, complaint handling or other activities and
tracking the data over time. Such information is necessary to contribute in achieving
problem resolution or problem prevention. Trending examines the processes as a
whole and enables the detection of potential problems as early as possible to plan
corrective and preventive actions.
4.4.2 Conducting Audits: QS requires audits to be conducted at planned intervals to
evaluate effective implementation and maintenance of the QS. Audits are also
required to determine that the processes and products meet established parameters
and specifications. Procedures should illustrate how auditors are trained in objective
evidence gathering, their responsibilities and auditing procedures. The scope and
methodology of the audit, selection of auditors and conduct of the audit should also
be in black and white. The records of audit findings should be maintained and
responsibilities assigned for follow up. The managers for responsible areas audited
should take timely actions to resolve audit findings.
4.4.3 Risk Management: Elements of risk should be considered in relation to the
intended use of a product, patient safety and ensuring availability of medically
necessary drug products. The management should assign priorities to activities or
actions based on risk assessment including both the probability of occurrence of harm
and the severity of that harm. Risk management is a tool in the development of
product specifications and Critical Process Parameters (CPP).

Quality System
4.4.4 Corrective action: It is a reactive approach to ensure that significant problems
do not recur. It is essential to document corrective actions followed by an
investigation and determine what actions will reduce the likelihood of a problem
recurring. It can be achieved by the following:
• Non-conformance reports and rejections
• Returns
• Complaints
• Internal and external audits
• Data and risk assessment related to operations and quality system processes
• Management review decisions
4.4.5 Preventive action: It is a proactive approach and an essential tool in the QS.
Succession planning, training, capturing institutional knowledge, and planning for
personnel, policy and process changes are preventive actions that will facilitate to
ensure that potential problems and root causes are identified, possible consequences
assessed and appropriate actions considered. The preventive action should be
evaluated and recorded and the system should be monitored for the effectiveness of
the action.
In summary, it is critical that the senior management should be involved in the
evaluation of the improvement process to keep continuance of the effectiveness and
efficiency of QS.
5. REFERENCES:
i. US-FDA
ii. ICH Q8 Guidance on Product Development
iii. ICH Q9 Guidance on Quality Risk Management
iv. ICH Q10 Guidance on Pharmaceutical Quality Systems

Draft Policy on Quality System as an Integrated Policy

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