US FDA GMP/cGMP 21 CFR Part 211

Subpart A - General Provisions

§ 211.1 - Scope.

§ 211.3 - Definitions.

Subpart B - Organization and Personnel

§ 211.22 - Responsibilities of quality control unit.

§ 211.25 - Personnel qualifications.

§ 211.28 - Personnel responsibilities.

§ 211.34 - Consultants.

Subpart C - Buildings and Facilities

§ 211.42 - Design and construction features.

§ 211.44 - Lighting.

§ 211.46 - Ventilation, air filtration, air heating and cooling.

§ 211.48 - Plumbing.

§ 211.50 - Sewage and refuse.

§ 211.52 - Washing and toilet facilities.

§ 211.56 - Sanitation.

§ 211.58 - Maintenance.

Subpart D - Equipment

§ 211.63 - Equipment design, size, and location.

§ 211.65 - Equipment construction.

§ 211.67 - Equipment cleaning and maintenance.

§ 211.68 - Automatic, mechanical, and electronic equipment.

§ 211.72 - Filters.

Subpart E - Control of Components and Drug Product Containers and Closures

§ 211.80 - General requirements.

§ 211.82 - Receipt and storage of untested components, drug product containers, and closures.

§ 211.84 - Testing and approval or rejection of components, drug product containers, and closures.

§ 211.86 - Use of approved components, drug product containers, and closures.

§ 211.87 - Retesting of approved components, drug product containers, and closures.

§ 211.89 - Rejected components, drug product containers, and closures.

 § 211.94 - Drug product containers and closures.

Subpart F - Production and Process Controls

§ 211.100 - Written procedures; deviations.

§ 211.101 - Charge-in of components.

§ 211.103 - Calculation of yield.

§ 211.105 - Equipment identification.

§ 211.110 - Sampling and testing of in-process materials and drug products.

§ 211.111 - Time limitations on production.

§ 211.113 - Control of microbiological contamination.

§ 211.115 - Reprocessing.

Subpart G - Packaging and Labeling Control

§ 211.122 - Materials examination and usage criteria.

§ 211.125 - Labeling issuance.

§ 211.130 - Packaging and labeling operations.

§ 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug

products.

§ 211.134 - Drug product inspection.

§ 211.137 - Expiration dating.

Subpart H - Holding and Distribution

§ 211.142 - Warehousing procedures.

§ 211.150 - Distribution procedures.

Subpart I - Laboratory Controls

§ 211.160 - General requirements.

§ 211.165 - Testing and release for distribution.

§ 211.166 - Stability testing.

§ 211.167 - Special testing requirements.

§ 211.170 - Reserve samples.

§ 211.173 - Laboratory animals.

§ 211.176 - Penicillin contamination.

Subpart J - Records and Reports

§ 211.180 - General requirements.

§ 211.182 - Equipment cleaning and use log.

§ 211.184 - Component, drug product container, closure, and labeling records.

§ 211.186 - Master production and control records.

§ 211.188 - Batch production and control records.

§ 211.192 - Production record review.

§ 211.194 - Laboratory records.

§ 211.196 - Distribution records.

§ 211.198 - Complaint files.

Subpart K - Returned and Salvaged Drug Products

§ 211.204 - Returned drug products.

§ 211.208 - Drug product salvaging.

Principles and guidelines of good manufacturing practice (GMP) for medicinal

products for human use as per Article 6 to Article 14 of Directive 91/356/EEC:

Chapter II of the Directive 91/356/EEC deals with principles and guidelines of GMP
under various ‘Articles’ as follows:
Article 6: Quality management
Article 7: Personnel
Article 8: Premises and equipment
Article 9: Documentation
Article 10: Production
Article 11: Quality control
Article 12: Work contracted out
Article 13: Complaints and product recall
Article 14: Self-inspection
Key concepts to GAMP 5:
1. Product and Process Understanding.
2. Lifecycle approach within QMS.
3. Scalable Lifecycle Activities.
4. Science Based Quality Risk Management.
5. Leveraging Supplier Involvement

The Master Validation Plan (MVP) is a document pertaining to the whole facility that
describes which equipment, systems, methods and processes will be validated and when
they will be validated. The document should provide the format required for each particular
validation document (Installation Qualification, Operational Qualification and Performance
Qualification for equipment and systems; Process Validation; Analytical Assay Validation),
and indicate what information is to be contained within each document. Some equipment
requires only installation and operational qualifications, and various analytical tests need to
establish only some performance parameters - this must be explained in the master protocol
along with some principles of how to determine which of the qualifications are required by
each, and who will decide what validations will be performed.
The Master Validation Plan should also indicate why and when revalidations will be
performed, either after changes or relocation of equipment or systems; changes to
processes or equipment used for processing; or for changes in assay methods or in
equipment used in tests.
If a new process or system is implemented, a Design Qualification (DQ) may be necessary.
Guidelines for such cases should be included in the Master Validation Plan. A Design
Qualification would be necessary when planning and choosing equipment or systems to
ensure that components selected will have adequate capacity to function for the intended
purpose, and will adequately serve the operations or functions of another piece of
equipment or operation.
For example: i) a water system must produce sufficient water of specified quality to serve
the requirements of the facility including production, testing, and as a source for steam or
for a second system producing higher quality water; ii) a steam generator must produce
sufficient steam of the correct quality to fulfill all the autoclaving needs and Steam-in-Place
(SIP) cleaning procedures of the facility; or iii) the equipment chosen for a particular
operation must have sufficient space and access for proper cleaning operations and
maintenance. The order in which each part of the facility is validated must be addressed in
the Master Validation Plan. For example the water system should be validated before
validating a piece of equipment that uses this water system. The IQ, OQ and PQ must be
performed in order: the master validation plan should indicate how to deal with any
deviations from these qualifications, and state the time interval permitted between each
validation.
USFDA GLP (GOOD LABORATORY PRACTICE)
Subpart A - General Provisions
Subpart B - Organization and Personnel
Subpart C - Facilities (Animal Care F/Animal Supply F/Lab operation area/F for tests)
Subpart D - Equipment
Subpart E - Testing Facilities Operation (SOPs)
Subpart F - Test and Control Articles
Subpart G - Protocol for and Conduct of a Nonclinical Laboratory Study
Subparts H-I [Reserved]
Subpart J - Records and Reports
Subpart K - Disqualification of Testing Facilities

GLP Control is summarized as follows:

1. General instructions
2. Areas of Expertise of the Facility
3. Establishment Inspections
4. Establishment Inspections
5. Establishment Inspections
6. Establishment Inspections
7. Establishment Inspections
8. Establishment Inspections
9. Establishment Inspections

GALP
8.1 LABORATORY MANAGEMENT 8.7 HARDWARE

8.2 PERSONNEL 8.8 COMPREHENSIVE TESTING

8.3 QUALITY ASSURANCE UNIT 8.9 RECORDS RETENTION

8.4 LIMS RAW DATA 8.10 FACILITIES

8.5 SOFTWARE 8.11 STANDARD OPERATING PROCEDURES

8.6 SECURITY
21 CFR PART 11
Subpart A - General Provisions
- Scope
- Implementation
Subpart B - Electronic Records
- Control for closed system
- Control for open system
- Signature/record linking
Subpart C - Electronic Signatures
- General requirement
- Electronic signature components and controls
- controls for identification codes/passwords

GDP Requirements –
1. Warehousing And storage
2. Temperature, Env, Stock Control
3. Personnel
4. Documentation
5. Premises
6. Equipment
7. Deliveries to Customers
8. Returns
9. Self Inspection
10. Stability Testing
WHO-GDP
General principles

Quality management Recalls Premises

Quality risk management Returned goods Stock control and rotation

Management review Equipment Personnel

Complaints Qualification and validation

Self-inspection. Documentation Activities and operations

Substandard and falsified products Inspection of storage and distribution facilities

TQM –

Key Principles

1. Compliance
2. Risk management
3. Continuous improvement
4. Customer focus
5. Employee empowerment
6. Data driven decision making
7. Supplier relationship

Validation

1. TAnalytical V
2. Equipment V – Instillation Q
Operational Q
Design Q
Performance Q
3. Cleaning V
4. Process V – Prospective V
Concurrent V
Retrospective V
Process Re-V

Stage1- Process Design

Stage2- Process Qualification

Stage3- Contd. Process verification

TYPES OF QUALIFICATION

process or equipment under qualification; that may affect the efficacy, quality

and or records of the product are properly qualified. Qualification includes

the following steps

● Design qualification (DQ)

● Component qualification (CQ)

● Installation qualification (IQ)

● Operational qualification (OQ)

● Performance qualification (PQ

● Design qualification (DQ)-

● Demonstrates that the proposed design (or the existing design for an

off-the-shelf item) will satisfy all the requirements that are defined and

detailed in the User Requirements Specification (URS).

● Satisfactory execution of the DQ is a mandatory requirement before

construction (or procurement) of the new design can be authorised.

● Installation qualification (IQ) –

● Demonstrates that the process or equipment meets all specifications,

is installed correctly, and all required components and documentation

needed for continued operation are installed and in place.

● Operational qualification (OQ) –

○ Demonstrates that all facets of the process or equipment are

operating correctly.

● Performance qualification (PQ) –

● Demonstrates that the process or equipment performs as intended in a

consistent manner over time.

● Component qualification (CQ) –

● Is a relatively new term developed in 2005.

● This term refers to the manufacturing of auxiliary components to ensure

that they are manufactured to the correct design criteria.

● This could include packaging components such as folding cartons,

shipping cases, labels or even phase change material.

● All of these components must have some type of random inspection to

ensure that the third party manufacturer's process is consistently

producing components that are used in the world of GMP at drug or

biologic manufacturers.
ISO 13485 (QMS)

Scope

1. Design and development

2. Control of monitoring and measuring devices
3. Validation of processes
4. Traceability
5. Control of non conforming prodcuts
6. CAPA
7. Risk management
8. Documentation

Implementation

1. Conduct gap analysis

2. Develop a project plan
3. Establish quality policy and objectives
4. Develop a quality manual
5. Implement QMS
6. Conduct internal audits
7. CAPA
8. Obtain certifications
9. Continual improvement

Quality Guidelines

Harmonisation achievements in the Quality area include pivotal milestones such as the
conduct of stability studies, defining relevant thresholds for impurities testing and a more
flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP)
risk management.
Q1A - Q1F Stability

Q2 Analytical Validation

Q3А - 03E Impurities

04A - 04B Pharmacopoeias

Q5A - Q5E Quality of Biotechnological Products

Q6A- 06B Specifications

Q7 Good Manufacturing Practice

Q8 Pharmaceutical Development

Q9 Quality Risk Management

010 Pharmaceutical Quality System

Q11 Development and Manufacture of Drug Substances

Q12 Lifecycle Management

Q13 Continuous Manufacturing of Drug Substances and Drug Products

Q14 Analytical Procedure Development

Safety Guidelines

ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like
carcinogenicity, genotoxicity and reprotoxicity. A recent breakthrough has been a non-
clinical testing strategy for assessing the QT interval prolongation liability: the single most
important cause of drug withdrawals in recent years.
S1A - S1C Carcinogenicity Studies
S2 Genotoxicity Studies
S3A - S3B Toxicokinetics and Pharmacokinetics
S4 Toxicity Testing
S5 Reproductive Toxicology
S6 Biotechnological Products
S7A - S7B Pharmacology Studies
S8 Immunotoxicology Studies
S9 Nonclinical Evaluation for Anticancer Pharmaceuticals
S10 Photosafety Evaluation
S11 Nonclinical Paediatric Safety
S12 Non-clinical Biodistribution Considerations for Gene Therapy Products
 Efficacy Guidelines

The work carried out by ICH under the Efficacy heading is concerned with the design,
conduct, safety and reporting of clinical trials. It also covers novel types of medicines
derived from biotechnological processes and the use of pharmacogenetics/
pharmacogenomics techniques to produce better targeted medicines.
E1 Clinical Safety for Drugs used in Long-Term Treatment
E2A - E2F Pharmacovigilance
E3 Clinical Study Reports
E4 Dose-Response Studies
E5 Ethnic Factors
E6 Good Clinical Practice
E7 Clinical Trials in Geriatric Population
E8 General Considerations for Clinical Trials
E9 Statistical Principles for Clinical Trials
E10 Choice of Control Group in Clinical Trials
E11 - E11A Clinical Trials in Paediatric Population
E12 Clinical Evaluation by Therapeutic Category
E14 Clinical Evaluation of QT
E15 Definitions in Pharmacogenetics / Pharmacogenomics
E16 Qualification of Genomic Biomarkers
E17 Multi-Regional Clinical Trials
E18 Genomic Sampling
E19 Safety Data Collection
E20 Adaptive Clinical Trials
E21 Inclusion of Pregnant and Breastfeeding Individuals in Clinical