Resource, &

Manufacturing Operations
Presented by: Bhojani Sofiya Sirajbhai
Guided by : Dr Rajashree Mashru
Subject: Audits and Regulatory Compliance
S.S.M.Pharm I
Resources

 The appropriate assignment of resources is essential and critical in a pharmaceutical

manufacturing environment.
 Inadequate staffing, training, manufacturing equipment and facilities, environmental
controls, analytical equipment, and other resources can be sources of variability leading
to the production of product that does not meet specified requirements.
 Modern quality system standards specifically address the issue of resources by
requiring the organization to determine and provide the human, infrastructure, and
work environment resources necessary for the quality system.
 The FDA discusses the need for adequate resources in developing, implementing, and
managing a quality system that complies with the cGMP regulations.

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Resources

 Management is responsible for identifying resource requirements and providing

resources accordingly, including providing training that is appropriate to the assigned
activities.
 Personnel should understand the impact of their activities on their assigned duties and
be familiar with cGMP requirements and the organization's quality system.
 Current quality system models employ a risk based and data - driven approach to the
development of QS system requirements to assure their adequacy.
 The FDA notes that the GMP regulations place as much emphasis on processing
equipment as testing equipment and contain specific requirements for the qualification,
calibration, cleaning, and maintenance of production equipment that may be a higher
standard than most non pharmaceutical quality system models.

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Resources

 The GMP regulations require the QU to be responsible for reviewing and approving all
initial design criteria and procedures pertaining to facilities and equipment and any
subsequent changes.
 In the control of outsourced operations, the cGMP regulations require that the QU
approve or reject products or services provided under a contract.
 Under current quality system models, the organization must follow a formal vendor
qualification process to qualify outsource providers and verify through inspection or
other appropriate means that the provider is capable of meeting the requirements of the
organization.
 To comply with the regulation, these operations should be conducted by the QU.

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 Table 1: 21 CFR cGMP Regulations Related to Resources
Quality System Element Regulatory Citation
1. General arrangements
2. Develop personnel Qualifications: § 211.25(a)
Staff number: § 211.25(c)
Staff training: § 211.25(a – b)
3. Facilities and equipment Buildings and facilities: § § 211.22(b),
211.28(c), 211.42 – 211.58, 211.173
Equipment: § § 211.63 – 211.72,
211.105, 211.160(b)(4), 211.182
Lab facilities: § 211.22(b)
4. Control outsourced operations Consultants: § 211.34
Outsourcing: § 211.22(a)

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Manufacturing Operations

 The FDA has identified four major elements of a QS approach to

manufacturing operations
 These are identified and compared to the cGMP requirements which are
follow:
1. Design and develop product and processes

2. Examine inputs

3. Perform and monitor operations

4. Address nonconformities 7
 Table 2: 21 CFR cGMP Regulations Related to Manufacturing Operations
Quality System Element Regulatory Citation
1. Design and develop product and Production: § 211.100(a)
processes
2. Examine Inputs Materials: § § 210.3(b), 211.80 – 211.94,
211.101,211.122, 211.125
3. Perform and monitor operations Production: § § 211.100, 211.103, 211.110,
211.111, 211.113
QC criteria: § § 211.22(a – c), 211.115(b),
211.160(a), 211.165(d), 211.188
QC checkpoints: § § 211.22 (a), 211.84(a),
211.87, 211.110(c)
4. Address nonconformities Discrepancy investigation: § § 211.22(a),
211.100, 211.115, 211.192, 211.198
Recalls: 21 CFR Part 7
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1. Design And Develop Product And Processes
 In a modern quality system manufacturing environment, the significant characteristics of the
product being manufactured should be defined and verified as meeting requirements from
design to delivery, and control should be exercised over all changes.
 The idea of controlling the design of both product and process is consistent with concepts
included in the FDA Pharmaceutical cGMPs for the 21st Century Initiative to assure product
safety that focus on the entire product life cycle.
 Documentation is required and can include the following:
 Resources and facilities used
 Procedures to carry out the process
 Identification of the process owner who will maintain and update the process as needed
 Identification and control of important variables
 Quality control measures, necessary data collection, monitoring, and appropriate controls for
the product and process
 Any validation activities, including operating ranges and acceptance criteria
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 Effects on related process, functions, or personnel
 The PAT guidance document describes a voluntary approach to the design, analysis, and
control of manufacturing processes that involves the timely (e.g., in - process)
measurement of critical quality and performance attributes of raw and in - process
materials and processes, with the goal of ensuring final product quality.
 PAT should ideally be initiated during the development stage and is intended to be
integrated into existing regulatory processes with timely communication with the FDA a
key element.
 In the PAT guidance, the FDA indicates that the desired state for pharmaceutical
manufacturing may be characterized as follows:
1. Product quality and performance are ensured through the design of effective and
efficient manufacturing processes
2. Product and process specifications are based on a mechanistic understanding of how
formulation and process factors affect product performance
3. Continuous real - time quality assurance
4. Relevant regulatory policies and procedures are tailored to accommodate
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the most
current level of scientific knowledge
2. Examine Inputs
 Inputs to manufacturing processes include any material that goes into the final product,
including materials purchased from vendors for use in manufacturing and in - process
materials.
 Manufacturing operations generally involve multiple processes conducted in a defined
manner to produce the finished product.
 Each process has a set of inputs and produces one or more outputs that may, in turn, be
an input to a subsequent process.
 Each process has an input – output relationship such that changes or variation in one or
more inputs will produce an attendant change in the output.
 Input specifications are established to assure that the final product meets its requirements.
 A robust quality system will ensure that all inputs to the manufacturing process are
suitable for use by establishing quality controls for the receipt and acceptance from
qualified vendors, production, storage, and use of all inputs.
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 The cGMP regulations require either testing or use of a certificate of analysis (COA) plus an
identity analysis for the release of materials for manufacturing.
 The quality systems approach additionally calls for initial supplier qualification based on an
objective evaluation and periodic auditing of suppliers based on risk assessment to verify the
adequacy of suppliers’ quality systems.
 Change control involves the evaluation of proposed changes in a systematic way to determine how
they would affect process outputs and ultimately the finished product and is an important element
of current quality system models.

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3. Perform and monitor operations
 The cGMP regulations require written production and process control procedures and specify
process control activities that must be performed and documented.
 Current quality system models also require written procedures, process verification and validation
as appropriate, the establishment of appropriate process control measures and documentation.
 A quality systems approach allows the manufacturer to more efficiently and effectively validate,
perform, and monitor operations and ensure that the controls are scientifically sound and
appropriate.
 One important aspect of the quality systems approach is the ongoing collection and analysis of
quality data to continuously evaluate quality system effectiveness.

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4. Address nonconformities
 A key component in any quality system is appropriately responding to nonconformities.
 The cGMP regulations require an investigation to be initiated and that the investigation,
conclusion, and follow - up be documented.
 The complete response to nonconformities should be risk based and can include the following
components:
 Assessment of how the nonconformity will affect the quality of the finished product
 Determine the cause of the nonconformity.
 Identify any actions needed to correct the cause and to prevent recurrence.
 Document the investigation, findings, and follow - up actions.
 Assess the effectiveness of follow - up actions.
 Repeat the cycle as needed.

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Reference

 Chapter 3.2- Role of Quality Systems and Audits in Pharmaceutical Manufacturing

Environment, Siegel E.B.; Barquest J.M.; et al, Pharmaceutical Manufacturing
Handbook, John Wiley Publication, Pg. No. 202-212
https://www.whistleblowerfirm.com/wp-content/uploads/2020/10/PHARMACEUTICA
L-MANUFACTURING-HANDBOOK-Regulations-and-Quality-1.pdf

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Thank you