How to build up a GMP Quality Manual ?

A quality manual is a document that a company writes to explain which portions of which
regulations are applicable to the company
(i.e. which regulations will be followed by the company.)
The regulations that are to be followed are based on the process(es) that are performed at
the company.
Not all portions of a regulation may be applicable to all companies.
Sometimes portions of various regulations are applicable (e.g. a medical device company
that also performs aseptic processing may follow portions of 21 CRF Part 820, Part 210,
and Part 211).

The company’s Quality Manual should outline which parts of which regulations are going
to be followed, how they are going to be followed, who is responsible for ensuring that the
regulations are followed, and which of the companies approved procedures address the
regulations to be followed. If all parts of a regulation are not going to be followed a
company may want to include a brief explanation as to why a part of a regulation is not
applicable to the company and therefore will not be outlined in the Quality Manual.

The Quality Manual should be written in general terms with minimal specifics. The format
of a Quality Manual is usually different than the format used for the company’s other
approved documents. The format should still include such things as a company’s logo and
name, version control, approval signatures, and confidential markings.

The following are examples of sections that a Quality Manual should contain:

1. Table of Contents
2. Introduction
3. Quality Policies and Objectives
4. Organization and Structure of Documentation
5. Company’s Products
6. References
7. Quality Policies for Specific Regulation Elements

Table of Contents:

A list of the sections contained within the Quality Manuel and the page each section begins
on.

Introduction:

A brief description of the company, the company’s purpose for writing a Quality Manual,
and a brief description of the scope of the Quality Manual.
Company Background:

List the name of the company, if it is publicly or privately owned, where the company is
located, the size of the facility, how the facility is used, the type of work that the company
does, what products are produced at the company, and what the products will be used for.

Purpose:

Provide general statements explaining why and how the Quality Manual will be used.

Example: “This manual will serve as a guide to company X quality policies and key
procedures, as well as to describe how these policies will be implemented.”

Example: “This Quality Manuel describes the quality management system that has been
established by Company X in order to meet regulatory requirements for the commercial
sale of products in the United States and in International Markets.”

Scope:

List the regulations that will be followed by the company as well as any portions of the
regulations that will not be followed. Provide a justification for why those portions of the
regulations are not going to be followed.

Example: “The system described in this manual is intended to meet general requirements
set forth in the United States Food and Drug Administration (FDA) Regulation according
to 21CFR Part 210 and 21CFR Part 211 as well as the relevant section of 21CFR Part
820.”

Example: “As a contract manufacturer of phase II materials Company X is not governed

by section Y of 21 CRF Part 211 however the company does look to 21 CRF Part 211 for
guidance in establishing and maintaining the quality system.”

Quality Policies and Objectives:

Include a brief statement about the approach that the company is taking in regards to
quality, (i.e. a Quality Mission Statement) and list the quality objectives of the company.
The quality objectives should not be numerous (five to seven is a typical number) and
should be briefly stated.

Example: Customer issues are addressed in a timely, professional, and thorough manner.

Example: Personnel are adequately trained in the job they perform

Example: Products and Services provided by our company are designed, manufactured,
and delivered to our customers and meet or exceed our customer requirements.
Organization and Structure of Documentation:

Provide an explanation as to how the documentation structure at your company is organized

and managed in relation to the applicable regulations.

Example: Documents related to the quality system are organized in a four level hierarchy
structure, are maintained in accordance with applicable regulatory requirements and our
company record retention policy, and are managed through a document change control
system.

Company’s Products:

This section should include a brief description of the products that are made and distributed
by the company including what the intended use of the products is to be. This description
should be similar to a marketing type summary in that it does not list proprietary or explicit
product information that would be detrimental to the company if persons outside the
company read the description. This section should provide enough detail to justify the
sections of the regulations that are and are not going to be followed.

References: A list of all the different regulations that were sited within the Quality Manual.

Example: FDA Title 21, Code of Federal Regulations Part 210 & 211, Current Good
Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs and
Finished Pharmaceuticals.

Quality Policies for Specific Regulation Elements:

This section will encompass the majority of the manual. It will include each regulation that
will be followed by the company, a brief description of how the company intends to follow
the regulation, and a list of the approved documents (by document name and number) that
the company has in place which specifically address/discuss the company’s policies and
objectives as stated in this section of the Quality Manual.

Example: Purchasing Controls; Procedures are established and maintained to ensure that
materials, supplies, and services impacting the Quality System and procured by Company
X purchasing department, conform to specified requirements.

1. Receiving Procedure SOP # XX. 01

2. Vendor Qualification Procedure SOP # XX. 01
3. Release of In-coming Goods Procedure SOP # XX. 01
4. ......

Example: Corrective and Preventive Action; At Company X, Corrective and Preventive

Actions are integral in a variety of programs. Whenever possible, these programs make an
effort to determine the root cause of the incident and to implement appropriate actions to
prevent the reoccurrence of the incident. Quality Assurance approves all Corrective and
Preventive plans and tracks their completion and effectiveness.
1. CAPA Procedure SOP # XX. 01
2. Material Review Board SOP # XX. 01
3. Failure Investigation Procedure SOP # XX. 01
4. .......
GMP Document Management System - a
brief Guide
A key aspect of a GMP facility is well written procedures. Procedures should be clear,
concise, unambiguous, and easy for employees to follow.
Well written procedures should not leave any room for misinterpretation. They should be
written in such a manner that anyone who is properly
trained and knowledgeable in the field can follow them as they are written.

There are various types of procedures that a GMP facility can have. The following is a list
and brief description of the most common types of documents.

Quality Manual

A global company document that describes, in paragraph form, the regulations and/or parts
of the regulations that the company is required to follow.

Policies

Documents that describe, in general terms and not with step-by-step instructions, how
overall guidelines for how specific GMP aspects
(such as security, documentation, health, and responsibilities) will be implemented.

Standard Operating Procedures (SOPs)

Step-by-step instructions for how to perform operational tasks or activities.

Batch Records

These documents are typically used and completed by the manufacturing department.
Batch records provide step-by-step instructions for production related tasks and activities as
well as include areas on the batch record itself for
documenting such tasks.

Test Methods

These documents are typically used and completed by the Quality Control Department.
Test Methods provide step-by-step instructions for testing supplies, materials, products and
other production related tasks and activities such as environmental
monitoring of the GMP facility.
Test Methods typically contain forms at the end of the procedure which are used for
documenting the testing and the results of the testing.

Specifications

Documents that list the requirements that a supply, material, or product must meet before
being released for use or sale.
The Quality Control Department will compare their test results to specifications to
determine if the testing passes.

Logbooks

Bound collection of forms used to document activities.

Typically logbooks are used for documenting the operation, maintenance, and calibration of
a piece of equipment Logbooks are also used for such
things are recording the monitoring of clean room activities, solution preparations,
deviation and corrective action assignment.

• Controlled Document Management System

•
•
•
• A controlled document template should be created for each document
type.
This template can then be used by all personnel who are writing
documents.
The following are examples of a document template:
A document number system also needs to be established for the various types of documents
that are created.

Document # Examples: GEN-001 (General SOPs), TM-001 (Test Methods), BR-001

(Batch Records), QP-001 (Quality Policy),

Standard Operating Procedure Template

Creation

Any knowledgeable employee should be able to write or revise documents as needed.

When revising a document the redline changes along with detailed justification of the
changes should be routed.
Routing

The document control function of QA is responsible for routing documents for review and
approval.
It is suggested that a pre-route be done to ensure that all affected parties are in agreement
with the document before it is submitted to QA.
There should be a documented process detailing how documents are submitted for review
and approval.
A controlled form listing all the changes made to the document, justification for the
changes, and a list of personnel who need to review
the document needs to be routed along with the document.
At a minimum the author’s manager, all affected department heads, and QA need to review
the document. Other Subject Matter Experts can be included.

Approval

Once all affected parties have agreed to the changes, document control will prepare the
document for approval.
All changes will be incorporated into the document.
For new documents the version # will be 00. For each revision of a document the version
number will increase (01, 02, 03, etc).
A master document will be routed for approval signatures.
Typically the approval signatures are the Author, the Department Head, and QA. QA must
be the last signature on all documents.
The approval signatures on Batch Records are typically the Head of Manufacturing and the
Head of QA.
Usually the approval signatures only appear on the first page of the document.
Once the master document has been signed, and effective date is stamped onto each page of
the document.
The effective date must be far enough in advance to allow for the document to be trained on
before it becomes effective (typically this is 5 days).

Distributing

On the effective day copies of the signed master document are routed to the affected
departments.
The departments will remove the old version and replace it the new version (for revised
documents).
If the document is new, there will be no replacement document to remove. The old versions
must be returned to document control.
On a periodic basis document control personnel should audit the binders to determine if
they contain the correct versions.
Each document binder should contain a table of contents and only those documents that the
department is responsible for.
A full set of all approved documents should be in the QA department as well as in a central
company location.
Archiving

Old revisions of documents will be stamped as superseded. No document revisions will be

discarded or altered.
A file will be maintained within QA that contains all the Superseded documents and the
signature approvals of personnel who agreed to the revisions.

Obsolete

If a document will no longer be used by any department in the company it can become
obsolete.
The document must be stamped as Obsolete and all copies removed from all document
binders.
It is a good idea to place a notice in the document stating that the document has been
Obsolete.

The role of QA , in regards to the document system, is one of management and overview.
QA ensures that all documents are maintained in a controlled fashion.
That all procedures being used within a company are approved by the appropriate subject
matter experts, are consistent with other documents,
and are the most current version. One way that QA ensures this is by being the last
signature on all approved documents.
All documents; current, obsolete, superseded, as well as all the history on the creation and
revision of the document are kept with in Quality Assurance.

Document Hierarchy

A company’s controlled GMP document system should be established in a hierarchical

manner starting with the general regulations and working downward
to more specific documents such as batch records. Refer to Diagram below for an example
of a hierarchical document system.

The regulations that a company is responsible for following (e.g. 21CFR210, 21CFR211,
21CFR820, etc) should be at the top of the document pyramid
and should govern the directives of the sub levels.

The level underneath the regulations, Level 1 documents (e.g. Quality Manual), should
break the regulations into parts specific to those
that the company is required to follow.
These documents should establish overall principles and guidelines for how the company
plans on developing, documenting, and implementing
a CGMP compliant quality system. Top level documents apply to all departments within a
CGMP compliant company and are not specific in nature.
The next level, Level 2, of documents on the hierarchy document pyramid should further
break down the parts of the regulations into specific subjects or topics.
These documents (e.g. Company Polices) should establish guidelines to which all
subordinate level procedures must comply with to ensure consistency across
departments.
Level 2 documents should not provide specific how to directive instructions or forms for
documenting data on but rather provide overall intentions
and guidelines governing critical programs or systems as well as explanations for the
rationale and program designs.
These documents will apply to all departments within a GMP compliant company.
(Example: Company X Quality Policy: GMP Personnel Responsibility. “To describe the
responsibility that personnel have in achieving and maintaining
compliance to Current Good Manufacturing Practices (GMP) and to the Quality System
that has been established at Company XXX.”)

Standard Operating Procedures (SOP) should be the next level in the document hierarchy
after Company Policy documents.
These types of documents should provide specific step-by-step instructions for how to
perform the operational tasks or activities that were generally
talked about in the previous levels.
(Example: SOP titled “Writing, Revising, Numbering, and Distributing Controlled
Documents”) Level 3 documents (e.g., SOPs)
should be department specific or function specific.

The last level of documents in a document hierarchical structure is the Level 4 documents.
These documents are the most specific in nature, (e.g. Batch Record, Test Methods,
Validation Procedures) they would apply to a specific department,
product, equipment, or process. Level 4 document provide step-by-step instructions for
production related tasks and activities as well as providing a
means for documenting such tasks such as data sheets, forms, or batch records.
The details outlined in these documents may override directions given in other level
documents.
(Example: The Company’s documentation SOP states to round numbers to 3 significant
figures but the batch record states to record all numbers
calculated in scientific notation. The requirements listed in the batch record are what are
followed.)

The document hierarchy pyramid is an example of one way to organize your company’s
documents.
More or less levels may be added/subtracted to meet your company’s specific needs.

Document Hierarchy Diagram

Regulations (CFR)
GMP Abbreviations
AAMI Association for the Advancement of
Medical Instrumentation

AAPS American Association of

Pharmaceutical Scientists

AdvaMed Advanced Medical Technology

Association

AESGP Association Européenne des

Specialités Grand Public

ANDA Abbreviated New Drug Application

ANSI American National Standards Institute

APIC Active Pharmaceutical Ingredients

Committee

ASQ American Society for Quality

BP British Pharmacopoeia

BSE Bovine Spongiform Encephalopathy

CDRH FDA Center for Devices and

Radiological Health

CEO Chief/Corporate Executive Officer

CEFIC European Chemical Industry Council

CPMP Committee of Proprietary Medicinal

Products (EU)

CVMP Committee of Proprietary Veterinary

Products (EU)

CRO Contract Research Organization

CTD Common Technical Document

(Register ICH)

DIA Drug Information Association (USA)

DOE Department of Energy (USA)

DSHEA Dietary Suplement Health and

Education Act (USA)

DSMA Division of Small Manufacturers

EIR Establishment Inspection Report

EMI Electro-Magnetic Interference

ESD Electro-static Discharge

EDQM European Directorate for the Quality

of Medicines

EGA European Generics Association

EMEA European Medicines Evaluation

Agency

EFPIA European Federation of

Pharmaceutical Industries Associations

EUR PH European Pharmacopoeia

(Commission)

FDA Food and Drug Administration (USA)

FDLI The Food and Drug Law

FEDESA Federation Européenne de la Santé

Animale

GCP Good Clinical Practice

GMO Genetically Modified Organisms

GMP Good Manufacturing Practice

GLP Good Laboratory Practice (For Safety
Evaluation)

GPIA Generic Pharmaceutical Industry

Association

HIMA The Health Industry Manufacturers

Association

ICH International Conference of

Harmonization

IDE Investigational Device Exemption

IEEE Institute of Electrical and Electronic

Engineering

IVD InVitro Diagnostic Devices

IFPMA International Federation of

Pharmaceutical Manufacturers Associations

IGPA International Generic Pharmaceutical

Association

IPEC International Pharmaceutical

Excipients Council

ISPE International Society for

Pharmaceutical Engineering

MCA Medicines Control Agency (UK)

MDMA Medical Device Manufacturers

Association

MDR Medical Device Reporting (21 CFR

Part 803 )

NAFL Notice of Adverse Findings

NAI No Action Indicated

NEMA National Electrical Manufacturers

Association

NIST National Institute for Standards and

Technology

NAFTA North American Free Trade

Agreement

NAPM National Association of

Pharmaceutical Manufacturers

NAS National Academy of Sciences (USA)

NCE New Chemical Entity

NDA New Drug Application

NIST National Institute of Science and

Technology (USA)

NPA National Pharmaceutical Alliance

NSE Not Substantially Equivalent

OAI Official Action Indicated

ODE FDA Office of Device Evaluation

ORA FDA Office of Regulatory Affairs

OC Oral Contraceptive

OEM Original Equipment Manufacturer

PCR Polymerase Chain Reaction

PDUFA Prescription Drug User Fee Act

(USA, 1992)

PEFRAS Pan European Federation of

Regulatory Affairs Society

PhARMA Pharmaceutical Association of

Research-based Manufacturers (PMA, USA)

PIC Pharmaceutical Inspection Convention

(EFTA)

PICS Pharmaceutical Inspection Cooperation

Scheme

PRP FDA's Problem Reporting Program

PTO Patent and Trademark Office (USA)

QSR Quality System Regulations (devices)

SE Substantially Equivalent

SMDA Safe Medical Devices

SMO Site Management Organization

SPC Summary of Product Characteristics or

Statistical Process Control

SRM Specified Risk Material (EU)

TSE Transmissible Spongiform

Encephalopathies (Veure BSE)

USP United States Pharmacopoeia

VAI Voluntary Action Indicated

VFA Verband der Forschender

Artzneitmittelherstellern

VOC Volatile Organic Compound

WHO World Health Organization (OMS)

WTO World Trade Organization

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