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11.4 Validation 265
Table 11.4 (Continued)
Cost of downtime/economical ranking Risk value Weighting Rating
High cost 2
Medium cost 1 2 0
Low cost 0
Quantity of duplicate systems (possible
problem with data Integrity where data
held and duplicated in several systems)
Risk value Weighting Rating
Greater than 5 systems 2
Between 2 and 5 systems 1 3 0
1system 0
Environmental impact (e.g. of systems
controlling sterilizing units)
Risk value Weighting Rating
High 2
Medium 1 1 0
Low 0
Assigned risk values in bold Rating = risk value × Weighting
manage and control their operations. Such systems are intended to be signicantly
congured depending on the operations undertaken at the site. They may be used
to issue complete work instructions, which could include calculations based on
specic batch properties,control the release of product at thevarious manufacturing
stages, and if validated to 21CFR Part 11, may be used to retain an electronic batch
record. Even where a system is not used to maintain an electronic record, it will
most likely be used to issue paper copies of work instructions and batch records for
manual completion. Thus, the accuracy and reliability of all data in the system are
vital as this is what a plant is likely to operate to rather than the original paper copy
procedures.
11.4.4 Methods Validation
The methods used for testing at various stages in the manufacturing process must
be validated to show that they are t for their intended application. For example,
a method may be capable of measuring an analyte to a high degree of accuracy
and precision in a series of standard solutions. However, the same level of perfor-
mance may not be guaranteed when it is used to measure the analyte in a reaction
mixture, due to the properties of the mixture or the presence of other compounds
that may interfere with the method. Thus, analytical methods will have to be appro-
priately qualied for the intended use in terms of specicity, linearity, measuring
range, accuracy, precision, detection limit, quantitation limit and robustness. Expla-
nations of these terms together with their relevance to dierent types of analytical
procedures are shown in Figure 11.14 and Table 11.5 respectively. Further informa-
tion may be found in ICH guideline Q2, which is devoted to the topic. While full
266 11 Good Manufacturing Practice (GMP)
Specicity
Specicity is the ability to assess unequivocally the analyte in the presence of components,
which may be expected to bepresent. Typicallythese might include impurities, degradants,
matrix, etc.
Accuracy
The accuracy of an analytical procedure expresses the closeness of agreement between the
value, which is accepted either as a conventional true value or an accepted reference value
and the value found. This is sometimes termed trueness.
Precision
The precision of an analytical procedure expresses the closeness of agreement (degree
of scatter) between a series of measurements obtained from multiple sampling of the
same homogeneous sample under the prescribed conditions. Precision may be considered
at three levels: repeatability (within run), intermediate precision (over time) and repro-
ducibility (inter laboratory).
Detection Limit
The detection limit of an individual analytical procedure is the lowest amount of analyte
in a sample, which can be detected but not necessarily quantitated as an exact value.
Quantitation Limit
The quantitation limit of an individualanalytical procedure is the lowest amount of analyte
in a sample, which can be quantitatively determined with suitable precision and accuracy.
Linearity
The linearity of an analytical procedure is its ability (within a given range) to obtain test
results, which are directly proportional to the concentration (amount) of analyte in the
sample.
Range
The range of an analytical procedure is the interval between the upper and lower concen-
tration (amounts) of analyte in the sample (includingtheseconcentrations)for which it has
been demonstrated that the analytical procedure has a suitable level of precision, accuracy
and linearity.
Robustness
The robustness of an analytical procedure is a measure of its capacity to remain unaected
by small, but deliberate variations in method parameters and provides an indication of its
reliability during normal usage.
Figure 11.14 Explanation of terms used to define the performance characteristics of an
assay.
validation testing is required for new methods, published pharmacopeial methods
will only require limited evaluation to demonstrate that the method has been set
up correctly.
11.4.5 Cleaning Validation
The cleaning of equipment that comes in contact with the product, such as reactors,
mixing vessels, pipe-work, pumps and tubing is another operation that is vital to
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11.4 Validation 267
Table 11.5 Applicability of performance characteristics to different analytical procedures.
Purpose of analytical
procedure
Identication Testing for impurities Assay
– dissolution
(measurement only)
– content/potency
Characteristics Quantitation Limit
Accuracy −+ − +
Precision
Repeatability −+ +(1) +
Interm. Precision −− − +(1)
Specicity (2) ++ + +
Detection Limit −−(3) +−
Quantitation Limit −+ − −
Linearity −+ − +
Range −+ − +
− signies that this characteristic is not normally evaluated.
+ signies that this characteristic is normally evaluated.
(1) In cases where reproducibility has been performed, intermediate precision is not needed.
(2) Lack of specicity of one analytical procedure could be compensated by other supporting
analytical procedure(s).
(3) May be needed in some cases.
prevent contamination due to carry-over of residues from previous products or
microbial growth. This may involve selecting equipment and procedures for clean-
ing in place (CIP) with various wash solutions, in preference to disassembly and
engaging in manual cleaning. One reason for choosing a CIP option is that it is likely
to deliver consistent performance, in contrast to manual operations, which may be
more prone to individual operator variation. Secondly, an absence of direct human
contact and exposure to the general environment makes it easier to obtain a sterile
environment.The eectiveness of all cleaningproceduresmustbe established by val-
idation studies. These may involve selecting combinationsof products that havevery
tight specications for contaminant carry-over, or which are sensitive to contami-
nation, or which are known to be particularly dicult to clean. Testing may involve
taking swabs from internal surfaces to check residue levels or microbial status as
appropriate.
11.4.6 Validation of Sterilisation Procedures
Pharmaceuticals for injection must be presented in a sterile form. Sterility may be
achieved by ltration through 0.22 μm lters under aseptic conditions, or by steam,
dry heat, radiation or gas sterilisation methods, which may be applied to packaged
products. Irrespective of the method, the process must be validated and monitored
268 11 Good Manufacturing Practice (GMP)
to assure its eectiveness. As discussed in Chapter 2 this is an example of a process
that cannot be assured by verication testing because of its destructive nature.
11.4.7 Water Purification System Validation
Water purication systems must be validated to demonstrate that they can product
the required water quality. The FDA have produced guidelines for commissioning
a water purication system, that requires various levels of monitoring as the
commissioning process moves from an initial two-week rst phase to a second
four-week phase, after which routine monitoring is acceptable.
11.5 GMP Requirements for Devices
In Europe, there are no specicGMP regulations for medical devices. However, man-
ufacturers will be operating to ISO 13485:2016, ‘Medical devices – Quality manage-
ment systems – Requirements for regulatorypurposes’, which has become a globally
recognised standard for device manufacturers to demonstrate thatthey satisfy essen-
tial requirements. This standard originally evolved from the more general ISO 9000
series of quality assurance standards, into a stand-alone standard, which through
various revisions is now somewhat divergent in structure from the current ISO9001
standard. The FDA issued current GMP regulations for medical devices in the form
of the Quality System Regulation (QSR) that may be found in Title 21 of the Code
of Federal Regulation, Part 820 (21 CFR 820). The QSR is based on the original ISO
quality standards, although the sequence of topics no longer match since the ISO
standards were revised. The topics covered by ISO13485 and the QSR are shown in
Figures 11.15 and 11.16. The FDA is proposing to amend Part 820, through incorpo-
rating by reference the quality management system requirements of ISO 13485 2016
so that compliance with the standard will be recognised as compliance with what
will then be referred to as the Quality Management System Regulation (QMSR). In
preparing the proposal the FDA mapped the existing QSR to the ISO standard as
outlined in Table 11.6.
By virtue of the broad diversity of products covered under the medical devices
umbrella, GMP regulations and standards for devices tend to be less specic than
their drug GMPs counterparts. However, itis expected that the manufacturer will use
risk analysis to identify specic measures that are appropriate to the manufacturing
process under consideration. In eect, this means that many of the GMP measures
applicable to drugs will also apply to devices. For example, if a manufacturer is pro-
ducing an implantable device, then the same levels of cleanliness and sterility as
required for an injectable biopharmaceutical will apply. Thus, device manufacturers
will often use drug GMP guidance as a basis for developing appropriate manufac-
turing conditions for devices. It is worthwhile to note that just as US drug GMPs
require the compilation of a master production and control record, US device regula-
tions require the preparation of an equivalent Device Master Record (DMR), which
should contain or reference all the procedures and specications necessary for its
manufacture.
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11.5 GMP Requirements for Devices 269
1. Scope
2.
Normative references
3.
Terms and denitions
4.
Quality management system
4.1 General requirements – Implement and maintain a quality system
4.2 Documentation requirements – Create quality policy, quality manual, proce-
dures, and document control and distribution function. Retain records for the
expected lifetime of the device or a minimum of 2 years
5.
Management responsibility
5.1 Management commitment – Show evidence of top management commitment to
quality
5.2 Customer focus – Determine and satisfy customer requirements
5.3 Quality policy – Have top management express quality intentions
5.4 Planning – Set quality objectives and plans to meet those objectives
5.5 Responsibility, authority and communication – Appoint a quality man-
ager, dene organisational structure and responsibilities, communicate quality
performance
5.6 Management review – Senior management to conduct regular reviews of the
quality system and its performance
6.
Resource management
6.1 Provision of resources – Provide resources to implement quality system and
meet
regulatory and customer requirement)
6.2 Human resources – Ensure appropriate qualications, education, training of per-
sonnel
6.3 Infrastructure – Provide appropriate facilities, equipment and supporting
services
6.4 Work environment and contamination control – Establish hygiene, clothing
and environmental conditions appropriate to operations
7.
Product realization
7.1 Planning of product realization – Plan and develop process for product manu-
facture based on risk analysis, and determine verication, validation, monitoring
test and inspection requirements
7.2 Customer-related processes – Review requirements before committingto supply,
communicate with customers on comments or complaints
7.3 Design and development – Establish design control process, See Unit 9
7.4 Purchasing – Qualify suppliers, establish material specications and verify pur-
chased product
7.5 Production and service provision – Operate production and service provision
under controlled conditions, maintain batch records, validation processes that can
not be veried, maintain identication and traceability of materials, address spe-
cic requirements for sterile products, provide suitable conditions for storage and
distribution
7.6 Control of monitoring and measuring equipment – Maintain and calibrate
measuring equipment
Figure 11.15 The main headings of the ISO 13485:2016 standard. Source: Adapted from
ISO, 2016.
270 11 Good Manufacturing Practice (GMP)
8. Measurement, analysis and improvement
8.1 General – Plan and implement monitoring, measurement, analysis and improve-
ment processes
8.2 Monitoring and measurement – Establish customer complaints/feedback and
internal audits processes, evaluate eectiveness of processes, verify product meets
acceptance criteria
8.3 Control of nonconforming product – Establish procedures for rework, reject, or
release under concession
8.4 Analysis of data – Analyse performance of quality system based on feedback, con-
formity of product to requirements, trends and supplier performance
8.5 Improvement – Implement Corrective Action, Preventative Action (CAPA) pro-
cedures, incorporating root cause investigation
Figure 11.15 (Continued)
Subpart A General Provisions
Sec. 820.1 Scope – Class II & III, plus a few Class I.
Sec. 820.3 Denitions.
Sec. 820.5 Quality System – Establish and maintain a quality system.
Subpart B Quality System Requirements
Sec. 820.20 Management responsibility– Establish quality policy and objectives, organ-
isational structure and responsibilities, appoint a quality manager, provide adequate
resources, conduct management reviews of the quality system and establish quality
plans and quality system procedures, including an overview of system.
Sec. 820.22 Quality audit – Conduct regular audits of the quality system.
Sec. 820.26 Personnel – Ensure appropriate qualications, education, training of
personnel.
Subpart C Design Controls
Sec. 820.30 Design controls – Establish design control process, See Unit 9.
Subpart D Document Controls
Sec. 820.40 Document controls – Establish procedures for document approval, revision
and distribution.
Subpart E Purchasing Controls
Sec. 820.50 Purchasing controls – Evaluate suppliers and establish material
specications.
Subpart F Identication and Traceability
Sec. 820.60 Identication – Identify components at all stages in the production process.
Sec. 820.65 Traceability – Use lot numbers for traceability of devices/components for
surgical implant or sustaining life.
Subpart G Production and Process Controls
Sec. 820.70 Production and process controls – Address production procedures and pro-
cess controls, changes to the process, environmental controls, clothing and hygiene of
personnel, prevention of contamination, suitability and layout of buildings, equipment
qualication, maintenance, periodic inspection, and adjustment, removal of unwanted
manufacturing materials from devices and automated (computer controlled) processes.
Figure 11.16 Headings of the Quality System Regulations (QSR) from 21 CFR Part 820.
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11.5 GMP Requirements for Devices 271
Sec. 820.72 Inspection, measuring and test equipment – Use traceable calibration stan-
dards and maintain calibration records for measuring equipment.
Sec. 820.75 Process validation – processes thatcan not be fully veried must bevalidated.
Subpart H Acceptance Activities
Sec. 820.80 Receiving, in-process, and nished device acceptance – Establish pro-
cedures for testing in coming goods, in process materials and nished product and
maintain records
Sec. 820.86 Acceptance status – Disposition of products shall be clearly displayed e.g. on
hold, approved, reject.
Subpart I Nonconforming Product
Sec. 820.90 Nonconforming product – Establish procedures for control on nonconform-
ing product, including rework and review of disposition.
Subpart J Corrective and Preventative Action
Sec. 820.100 Corrective and preventative action – Implement Corrective Action, Pre-
ventative Action (CAPA) procedures, incorporating root cause investigation.
Subpart K Labelling and Packaging Control
Sec. 820.120 Device labelling – Ensure legibility and durability of labels, inspect labels
before release from storage, and take measures to prevent mix-up.
Sec. 820.130 Device packaging – Packaging must provide adequate protection of the
device.
Subpart L Handling, Storage, Distribution, and Installation
Sec. 820.140 Handling – Establish procedures to prevent mix-ups, damage or deteriora-
tion during handling.
Sec. 820.150 Storage – Establish procedures for proper storage and control.
Sec. 820.160 Distribution – Establish procedures for distribution and maintain distribu-
tion records.
Sec. 820.170 Installation – Establish procedures for correct installation, where applicable.
Subpart M Records
Sec. 820.180 General requirements – Retain records for the expected shelf life of the
device or a minimum of 2 years after last distribution.
Sec. 820.181 Device master record – Compile or refer to procedures and specications
for device manufacture.
Sec. 820.182 Device history record – Maintain the production records for each batch of
devices.
Sec. 820.186 Quality system record – Compile or refer to location of general procedures
relating to the quality system.
Sec. 820.198 Complaint les – Maintain complaint les, investigate and assess if there
are reporting obligations, keep copies of les available in the US either at manufacturer
or initial distributor site.
Subpart N Servicing
Sec. 820.200 Servicing – Maintain servicing procedures where applicable.
Subpart O Statistical Techniques
Sec. 820.50 Statistical techniques – Use appropriate statistical methods for data analysis
and sampling plans.
Figure 11.16 (Continued)
272 11 Good Manufacturing Practice (GMP)
Table 11.6 High-level summary of 21 CFR Part 820 proposed rule differences and
additions.
Current part 820
a)
ISO 13485 requirements
a)
Proposed rule
SubpartA–General
Provisions
Clause 1. Scope,
Clause 4. Quality Management System.
Requirements
substantively similar.
SubpartB–QS
Requirements
Clause 4. Quality Management System,
Clause 5. Management Responsibility,
Clause 6. Resource Management,
Clause 8. Measurement, Analysis, and
Improvement
Requirements
substantively similar.
SubpartC–Design
Controls
Clause 7. Product Realization Requirements
substantively similar.
Subpart D – Document
Controls
b)
Clause 4. Quality Management System Dierences addressed
in 820.35.
Subpart E – Purchasing
Controls
Clause 7. Product Realization Requirements
substantively similar.
Subpart F – Identication
and Traceability
Clause 7. Product Realization Requirements
substantively similar.
SubpartG–Production
and Process Controls
Clause 4. Quality Management System,
Clause 6. Resource Management,
Clause 7. Product Realization.
Requirements
substantively similar
Subpart H – Acceptance
Activities
Clause 7. Product Realization,
Clause 8. Measurement, Analysis, and
Improvement
Requirements
substantively similar.
Subpart
I – Nonconforming
Product
Clause 8. Measurement, Analysis, and
Improvement.
Requirements
substantively similar.
Subpart J – Corrective
and Preventive Action
Clause 8. Measurement, Analysis, and
Improvement
Requirements
substantively similar
SubpartK–Labelingand
Packaging Control
Clause 7. Product Realization Dierences addressed
in 820.45
SubpartL–Handling,
Storage, Distribution,
and Installation.
Clause 7. Product Realization Requirements
substantively similar
Subpart M – Records Clause 4. Quality Management System Dierences addressed
in 820.35
Subpart N – Servicing Clause 7. Product Realization Dierences addressed
in 820.35
Subpart O – Statistical
Techniques
Clause 7. Product Realization,
Clause 8. Measurement, Analysis, and
Improvement.
Requirements
substantively similar
a) This table is not intended to be a requirement-by-requirement analysis, but a higher-level
mapping of the totality of the subparts and clauses of the standard and the QS regulation for
reference purposes only.
b) It’s important to note that while there are dierences specically identied in subpart D,
document requirements exist in most subparts and clauses of the standard and the QS
Regulation.
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11.7 Further Reading 273
11.6 Chapter Review
Good manufacturing practices (GMPs) have been developed to ensure that drugs
and devices are manufactured to the requisite standards of cleanliness, integrity and
quality. These are drawn from the general principles ofquality management systems,
which have been extended toaddress specic aspects that arenecessary to ensure the
quality of such products. GMP requirements generally increase as product reaches
the nal stages in the manufacturing process. Validation of facilities, equipment,
systems and processes is central to establishing GMP operations.
11.7 Further Reading
EU GMP Regulations
Directive 2003/94/EC laying down the principles and guidelines of good manufacturing
practice in respect of medicinal products for human use and investigational
medicinal products for human use
Directive 91/412/EEC laying down the principles and guidelines of good manufacturing
practice for veterinary medicinal products
Regulation No. 1252/2014 laying down the principles and guidelines of good
manufacturing practice for active substances for medicinal products for human use,
including active substances intended for export
The Rules Governing Medicinal Products in the European Union, Volume 1,
Legislation Human, Volume 5, Legislation Veterinary
https://ec.europa.eu/health/medicinal-products/eudralex_en
EU GMP Guidance
The Rules Governing Medicinal Products in the European Union, Volume 4, Medicinal
Products for Human and Veterinary Use: Good Manufacturing Practice
https://ec.europa.eu/health/medicinal-products/eudralex_en
US GMP Regulations
21 CFR Part 210, current Good Manufacturing Practice in Manufacturing, Processing,
Packing, or Holding of Drugs, General Requirements and,
21 CFR Part 211, current Good Manufacturing Practice for Finished Pharmaceuticals
21 CFR Part 820 Quality System Regulation Medical Devices; current Good
Manufacturing Practice
https://www.ecfr.gov/
Harmonised GMP Guidelines
ICH Guideline: Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients
www.ich.org
Process Validation
Guidance Globally Harmonised Task Force Guidance: Quality Management
Systems – Process Validation
274 11 Good Manufacturing Practice (GMP)
https://www.imdrf.org/FDA Guidance: Guideline on general principles of process
validation
www.fda.gov
Methods Validation
ICH Guideline: Q2 Validation of Analytical Procedures: Text and Methodology
www.ich.org
Computer System Validation
US Code of Federal Regulations 21 CFR Part 11
FDA Guidance: Guidance for Industry Part 11, Electronic Records; Electronic
Signatures – Scope and Application
www.fda.gov
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