Professional Documents
Culture Documents
2007
GUIDANCE DOCUMENT
REFERENCE VERSION
Author:
Title: Company:
Regulatory Consultant Validation in Partnership Ltd.
Doc. Ref. : SGD-105-CLN Rev. 10 Guidance Document Page : 2 of 176
Author : Validation in Partnership Ltd. Cleaning Processes and Cleaning Validation Date: : 25 May 2007
DOCUMENT HISTORY
01 September 2000
02 August 2001
03 February 2002
04 October 2002
05 November 2003
06 December 2004
07 January 2005
08 February 2006
09 March 2007
10 May 2007
Since 1995, Validation in Partnership has been an entirely independent organisation specialising in the successful
management and support of validation and CGMP compliance projects for the life science industries supplying the
European and American markets. With our proven in-house project staff and extensive network of vetted quality
contract personnel, we pride ourselves on a pragmatic approach that focuses effort on process critical areas to
ensure the optimum business solution to any compliance challenge.
Supported by the most extensive regulatory database in existence, courtesy of which this guidance document has
been compiled, our team and clients are secure in the knowledge they have instant access to up-to-the-minute
regulatory fact, and our state of the art automated document generation system ensures the rapid delivery and
consistent quality of your protocols and reports.
Whatever your requirement, ...
TABLE OF CONTENTS
1. AUTHOR’S NOTE
This guidance document is one in a series produced by Validation in Partnership Limited to assist
personnel in the life science industries in obtaining the regulatory perspective surrounding specific
aspects of their work.
We have long recognised that one of the issues in our industry is not that we do not possess sufficient
regulatory guidance on specific topics, but that we possess too much, albeit in the wrong format to
support its efficient use. Mountains of guidance documents, directives, warning letters and
establishment inspection reports cover a multitude of topics in a multitude of formats.
In creating this guidance document, we have used our regulatory database, the most extensive and
searchable in existence, to extract individual statements from over 900 regulatory documents and
compile them under logical headings to present them in a more usable form. The end product is not
intended to steer the reader through the process of developing cleaning procedures and cleaning
validation packages, but simply to highlight the regulatory points he or she will need to consider along
the way.
Indeed, there are certain points, FDA 483 inspectional observations and warning letter extracts within
the guide, with which the author does not concur. However, since each one has been derived from a
regulatory information source, they have been included for consideration. It is for this reason that each
regulatory point has been provided with sufficient source reference to enable the reader to further
investigate any point of contention in the context, in which the statement was made.
2. PURPOSE
To provide the regulatory perspective on the development of cleaning processes and cleaning validation
packages to meet the requirements of both the American (references shown in blue) and European
(references shown in red) regulatory bodies.
3. SCOPE
This guidance is applicable to the cleaning of facilities, equipment and instrumentation used in the
manufacture of finished pharmaceuticals and biological products (medicinal products), and active
pharmaceutical ingredients (APIs).
4. INTRODUCTION
Cleaning plays a crucial role in maintaining compliant pharmaceutical and biological product
manufacturing operations, and, as you will see, the regulators have quite a lot to say about it. The
regulatory requirements for cleaning, as applicable to a company, should also define its scope for
cleaning validation. After all, no cleaning process can be verified as effective unless validated. Effective
cleaning ensures that the risk of contamination, caused by batch to batch residues, cleaning agents or
the unintentional transfer of one process component or material residue into a subsequent product, is
minimised. Cleaning validation, which provides documented evidence that the cleaning procedure/
process is consistently capable of removing these potential contaminants to meet predetermined levels
of cleanliness, is the easiest thing in the world if, and only if, the cleaning process has been correctly
developed.
This ninth revision of the guidance document has been compiled from a detailed review of:
• over 900 regulatory texts
• over 20,000 regulatory records
• over 4,200 warning letter extracts
• over 3,100 FDA 483 observations
The end product comprises more than 450 points for consideration when developing procedures and
protocols associated with the areas of cleaning and cleaning validation. For ease of reference, the
points are collated under logical headings and sub-headings, although it is appreciated that the grouping
of the points is subjective. The term "points for consideration" should be emphasised, as the document
is intended to form a series of regulatory prompts rather than a definitive list of word for word
requirements.
Each paragraph within the guide is supported by one or more regulatory references. American
references are shown in blue, European references are shown in red and references applicable to both
regulatory bodies are shown in green.
Although this guide incorporates the latest annexes to the EU Guide to Good Manufacturing Practice,
Eudralex Volume 4, the author has chosen to include a number of extracts from selected superseded
documents (marked SUPERSEDED!) alongside those from the latest versions. The author believes that
the earlier texts contain a number of useful prompts that have been omitted from the latest documents.
5.1 Premises
1. Premises must be located, designed, constructed, adapted and maintained to permit effective
cleaning in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse
effect on the quality of products.
Selected FDA 483 Observations (July 2006)
Sterile Product Manufacture
[VIP ID: 194012]
“Buildings used in the manufacture, processing, placing, or holding of a drug product should have a suitable
construction to facilitate cleaning, maintenance, and proper operations.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PRINCIPLE
[VIP ID: 185552]
“Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to
be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and
maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the
quality of products.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 6 - MANUFACTURE OF MEDICINAL GASES
3. PREMISES AND EQUIPMENT
3.1 Premises
3.1.2
[VIP ID: 186472]
“…Premises should be clean and tidy to encourage orderly working and adequate storage.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 14 - MANUFACTURE OF PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA
PREMISES AND EQUIPMENT
6
[VIP ID: 186990]
“The premises used for the collection of blood or plasma should be of suitable size, construction and location to
facilitate their proper operation, cleaning and maintenance.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 2 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE
PREMISES AND EQUIPMENT
15
[VIP ID: 186218]
“The layout and design of production areas and equipment should permit effective cleaning and decontamination
(e.g. by fumigation).”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart C -- Buildings and Facilities
Sec. 211.42 Design and construction features
(a)
[VIP ID: 18]
“Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of
suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.”
PE 005-2
PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004)
7. PREMISES
7.1
[VIP ID: 185030]
“Premises should be located, designed, constructed, utilised and maintained according to the intended activity. The
planning and layout should be designed to permit operations to take place in a logical order corresponding to the
sequence of operations. Premises should be designed to permit effective cleaning, sanitisation and maintenance
and to minimise the risk of errors.”
PI 008-2
PIC/S GUIDANCE DOCUMENT FOR INSPECTORS
PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
(INSPECTION GUIDE) (July 2004)
13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
13.2 PREMISES AND HYGIENE
13.2.8
[VIP ID: 189270]
“The layout of premises and equipment must permit effective cleaning and maintenance in order to avoid cross
contamination and build up of dust and dirt (GMP 3, principle). Therefore the walls, floors and ceilings should be
smooth, free from cracks and open joints and should permit easy and effective cleaning and if necessary
disinfection (GMP 3.9.).”
COMMISSION DIRECTIVE 2003/94/EC OF 8 OCTOBER 2003 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 (October 2003)
Article 8
Premises and equipment
2
[VIP ID: 67330]
“Premises and manufacturing equipment shall be laid out, designed and operated in such a way as to minimise the
risk of error and to permit effective cleaning and maintenance in order to avoid contamination, cross contamination
and, in general, any adverse effect on the quality of the product.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
4. BUILDINGS AND FACILITIES
4.1 Design and Construction
4.10
[VIP ID: 24532]
“Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and
constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture.
Facilities should also be designed to minimize potential contamination. Where microbiological specifications have
been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable
microbiological contaminants as appropriate.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.1 Design and Construction
4.10
[VIP ID: 153640]
“Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and
constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture.
Facilities should also be designed to minimize potential contamination. Where microbiological specifications have
been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable
microbiological contaminants as appropriate.”
• Additional consideration should be given to the design of premises, inspection/test methods and
acceptance limits to be used after cleaning for investigational medicinal products where the toxicity,
potency and sensitising potential are not be fully understood.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS
PREMISES AND EQUIPMENT
5
[VIP ID: 186860]
“The toxicity, potency and sensitising potential may not be fully understood for investigational medicinal products
and this reinforces the need to minimise all risks of cross-contamination. The design of equipment and premises,
inspection / test methods and acceptance limits to be used after cleaning should reflect the nature of these risks.
Consideration should be given to campaign working where appropriate.”
2. Building used in the manufacture, processing, packing, or holding of a drug product should be
maintained in a clean and sanitary condition and should be free of infestation by rodents, birds,
insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be
held and disposed of in a timely and sanitary manner.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart C -- Buildings and Facilities
Sec. 211.56 Sanitation
(a)
[VIP ID: 47]
“Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a
clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects, and other
vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and
sanitary manner.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
4. BUILDINGS AND FACILITIES
4.7 Sanitation and Maintenance
4.70
[VIP ID: 24555]
“Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept
in a clean condition.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.7 Sanitation and Maintenance
4.70
[VIP ID: 153870]
“Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept
in a clean condition.”
• Sample areas should be cleaned before and after different raw material components are sampled.
Selected FDA 483 Observations (February 1999)
Sterile Product Manufacture
[VIP ID: 7075]
“Sample areas should be cleaned before and after different raw material components are sampled.”
3. Premises should be cleaned and, where applicable, disinfected according to detailed written
procedures.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PREMISES - General
3.2
[VIP ID: 185556]
“Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any
hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed
written procedures.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
2. QUALITY MANAGEMENT
2.3 Responsibility for Production Activities
(para 1)
(5)
[VIP ID: 24512]
“The responsibility for production activities should be described in writing, and should include but not necessarily
be limited to:
5. Making sure that production facilities are clean and when appropriate disinfected;”
• Written procedures should be established assigning responsibility for sanitation and describing the
cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and
facilities.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
4. BUILDINGS AND FACILITIES
4.7 Sanitation and Maintenance
4.71
[VIP ID: 24556]
“Written procedures should be established assigning responsibility for sanitation and describing the cleaning
schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.7 Sanitation and Maintenance
4.71
[VIP ID: 153880]
“Written procedures should be established assigning responsibility for sanitation and describing the cleaning
schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.”
4. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses
and a minimum of projecting ledges, shelves and cupboards. Doors should be designed to avoid
those uncleanable recesses; sliding doors may be undesirable for this reason.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS
PREMISES
23
[VIP ID: 186044]
“To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum
of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable
recesses; sliding doors may be undesirable for this reason.”
• Pipework, light fittings, ventilation points, ducts and other utilities should be installed so that they do
not create recesses, unsealed openings and surfaces which are difficult to clean.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PREMISES - Production Area
3.10
[VIP ID: 185572]
“Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of
recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from
outside the manufacturing areas.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS
PREMISES
25
[VIP ID: 186048]
“Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and
surfaces which are difficult to clean.”
• In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to permit
the repeated application of cleaning agents, and disinfectants where used.
Extracted from FDA warning letter VLN# 06200780 (January 2007)
USA
05-Jan-07
2. a.
[VIP ID: 194658]
“"Failure to have adequate building design and construction used in manufacture, processing, packing, or holding
of drug products to facilitate cleaning, maintenance, and proper operations. [21 CFR § 211.42(a)]
For example,
a. Your firm uses drop ceiling panels of porous, drywall-like material that is not easily cleaned in the formulation
room (Class 10,000), entry room (Class 100,000), and processing room (Class 100,000). Numerous ceiling tiles were
not seated flush with the metal frame revealing gaps between the ceiling tiles and the metal frame."”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP)
DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT
B. Facilities
2. Aseptic Processing Area
para 2
[VIP ID: 187392]
“We recommend that conditions in the room where aseptic manipulations are conducted not present a challenge to
the operating capability of the aseptic workstation. For example, the room should not be carpeted nor have
overhanging pipes or hanging light fixtures. All areas of the production and processing room should be easily
accessible for cleaning. Surfaces of the walls, floors, and ceilings in the aseptic work areas should be easily
cleaned. Cleaning should be performed frequently to ensure consistent control of the environmental quality. In
addition, the aseptic processing area (e.g., LAFW) should be situated in the section of the room with the lowest
traffic and lowest activity. Cartons and boxes should not be stored or opened in the production area to minimize
ingress of dust and particulate into the aseptic work area.”
• Where starting and primary packaging materials, intermediate or bulk products are exposed to the
environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and
open joints, and should not shed particulate matter and should permit easy and effective cleaning
and, if necessary, disinfection.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PREMISES - Production Area
3.9
[VIP ID: 185570]
“Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment,
interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not
shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.”
PI 012-2
RECOMMENDATION ON STERILITY TESTING (July 2004)
8. STERILITY TEST FACILITIES
8.3 CLEAN ROOM FITTINGS AND SURFACES
8.3.2
[VIP ID: 190274]
“The joints between ceiling/walls/floor should be coved to facilitate cleaning.”
5. Open channel drains should be avoided where possible, but if necessary, they should be shallow to
facilitate cleaning and disinfection.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PREMISES - Production Area
3.11
[VIP ID: 185574]
“Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but
if necessary, they should be shallow to facilitate cleaning and disinfection.”
6. When equipment maintenance has been carried out within the clean area, the area should be
cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the
required standards of cleanliness and/or asepsis have not been maintained during the work.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL
PRODUCTS (September 2003)
Equipment
34
[VIP ID: 63270]
“When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected
and / or sterilised where appropriate, before processing recommences if the required standards of cleanliness and /
or asepsis have not been maintained during the work.”
7. Adequate, clean washing and toilet facilities should be provided for personnel.
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.1 Design and Construction
4.15
[VIP ID: 153690]
“Adequate, clean washing and toilet facilities should be provided for personnel. These washing facilities should be
equipped with hot and cold water as appropriate, soap or detergent, air driers or single service towels. The washing
and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for
showering and/or changing clothes should be provided, when appropriate.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.5 Lighting
4.50
[VIP ID: 153850]
“Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.”
9. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing
operations, packaging of dry products), specific provisions should be taken to facilitate cleaning.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PREMISES - Production Area
3.14
[VIP ID: 185580]
“In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of
dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 7 - MANUFACTURE OF HERBAL MEDICINAL PRODUCTS
PREMISES
Storage areas
2
[VIP ID: 186614]
“Special attention should be paid to the cleanliness and good maintenance of the storage areas particularly when
dust is generated.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 7 - MANUFACTURE OF HERBAL MEDICINAL PRODUCTS
PREMISES
Production area
4
[VIP ID: 186618]
“Specific provisions should be taken during sampling, weighing, mixing and processing operations of crude plants
whenever dust is generated, to facilitate cleaning and to avoid cross-contamination, as for example, dust extraction,
dedicated premises, etc.”
10. Dedicated production areas should be considered when material of an infectious nature or high
pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents)
unless validated inactivation and/or cleaning procedures are established and maintained.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
4. BUILDINGS AND FACILITIES
4.4 Containment
4.41
[VIP ID: 24550]
“Dedicated production areas should also be considered when material of an infectious nature or high
pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless
validated inactivation and / or cleaning procedures are established and maintained.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.4 Containment
4.41
[VIP ID: 153820]
“Dedicated production areas should also be considered when material of an infectious nature or high
pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless
validated inactivation and/or cleaning procedures are established and maintained.”
11. Reception areas should be designed and equipped to allow containers of incoming materials to be
cleaned where necessary before storage.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
PREMISES - Storage Areas
3.20
[VIP ID: 185592]
“Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be
designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.”
12. Before packaging operations are begun, steps should be taken to ensure that the work area is
clean.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 5
PRODUCTION
PACKAGING OPERATIONS
5.45
[VIP ID: 185792]
“Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines,
printing machines and other equipment are clean and free from any products, materials or documents previously
used, if these are not required for the current operation. The line-clearance should be performed according to an
appropriate check-list.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 4
DOCUMENTATION
BATCH PACKAGING RECORDS
4.18
[VIP ID: 185678]
“Before any packaging operation begins, there should be recorded checks that the equipment and work station are
clear of previous products, documents or materials not required for the planned packaging operations, and that
equipment is clean and suitable for use.”
13. Multi-product facilities should have cleaning and testing procedures in place that ensure prevention
and/or detection of contamination by adventitious agents. To the extent possible, dedicated
equipment and/or disposable parts (e.g., tubing) is recommended. For multi-product areas
procedures should be established to prevent cross-contamination and demonstrate removal of the
previously manufactured product from shared equipment and work surfaces, especially if live viral
and vector processing occurs in a production area.
GUIDANCE FOR INDUSTRY
INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1
DRAFT GUIDANCE (January 2006)
VI. SPECIAL PRODUCTION SITUATIONS
C. Biological and Biotechnological Products
2. Multi-Product Facilities
[VIP ID: 183910]
“In addition to the recommendation in section VI.B, we recommend that multi-product facilities have cleaning and
testing procedures in place that ensure prevention and/or detection of contamination by adventitious agents. To the
extent possible, dedicated equipment and/or disposable parts (e.g., tubing) is recommended. For multi-product
areas, we recommend that procedures be established to prevent cross-contamination and that demonstrate removal
of the previously manufactured product from shared equipment and work surfaces, especially if live viral and vector
processing occurs in a production area.”
14. Bioburden inhibition studies should be performed for the sanitisation of critical production areas
(e.g. filling lines).
Selected FDA 483 Observations (July 1999)
Sterile Product Manufacture
[VIP ID: 7199]
“Bioburden inhibition studies should be performed for the sanitization of critical production areas (e.g. filling lines).”
5.2 Equipment
1. Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of
appropriate design, adequate size, and suitably located to facilitate its cleaning.
Extracted from FDA warning letter CIN-07-30670-09 (January 2007)
USA
11-Jan-07
4)
[VIP ID: 194708]
“Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design
to facilitate operations for its intended use and for its cleaning and maintenance. [21 CFR § 211.63] For example, CP-
2 packaging line was modified in a manner that made it difficult for employees to remove the line cover. As a result,
the line cover is not removed during line clearance operations and is only removed during preventative
maintenance. Per firm personnel, unit dose strips can become caught in this area and are routinely found during
maintenance.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.63 Equipment design, size and location
[VIP ID: 52]
“Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate
design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and
maintenance.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.1 Design and Construction
5.10
[VIP ID: 24558]
“Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size,
and suitably located for its intended use, cleaning, sanitization (where appropriate), and maintenance.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.1 Design and Construction
5.10
[VIP ID: 153900]
“Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size,
and suitably located for its intended use, cleaning, sanitization (where appropriate), and maintenance.”
• Pipework systems, valves and vent filters should be properly designed to facilitate cleaning and
sterilisation.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 2 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE
PREMISES AND EQUIPMENT
17
[VIP ID: 186222]
“Pipework systems, valves and vent filters should be properly designed to facilitate cleaning and sterilisation. The
use of "clean in place" and "sterilise in place" systems should be encouraged. Valves on fermentation vessels
should be completely steam sterilisable. Air vent filters should be hydrophobic and validated for their scheduled life
span.”
• Tanks, containers, pipework and pumps should be designed and installed so that they may be
readily cleaned and if necessary sanitised.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 9
PREMISES AND EQUIPMENT
2
[VIP ID: 186646]
“Tanks, containers, pipework and pumps should be designed and installed so that they may be readily cleaned and
if necessary sanitised. In particular, equipment design should include a minimum of dead-legs or sites where
residues can accumulate and promote microbial proliferation.”
• Washing and cleaning equipment should be chosen and used in order not to be a source of
contamination.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
EQUIPMENT
3.37
[VIP ID: 185626]
“Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.”
PI 008-2
PIC/S GUIDANCE DOCUMENT FOR INSPECTORS
PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
(INSPECTION GUIDE) (July 2004)
13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
13.3 EQUIPMENT
13.3.2
[VIP ID: 189286]
“Washing and cleaning equipment should be chosen and used in order not to be a source of contamination (GMP
3.37). Therefore cleaning equipment should be stored separately and not within production or product storage
areas.”
• The design of the equipment should be carefully examined and critical areas (those hardest to
clean) should be identified, particularly in large systems that employ semi-automatic or fully
automatic clean-in-place (CIP) systems.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.6 Equipment
7.6.1
[VIP ID: 188678]
“The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be
identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.”
• The use of 'clean in place' and 'sterilise in place' systems should be encouraged.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL
PRODUCTS FOR HUMAN USE (January 1993)
Premises and Equipment
17.
[VIP ID: 1530]
“…The use of 'clean in place' and 'sterilise in place' systems should be encouraged.”
• Particular attention should be paid to equipment design and qualification, validation and
reproducibility of cleaning-in-place when dealing with Blow-Fill-Seal technology.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL
PRODUCTS (September 2003)
Blow/fill/seal technology
10
(para 2)
[VIP ID: 62910]
“Because of this special technology particular attention should be paid to, at least the following: equipment design
and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background
cleanroom environment in which the equipment is located, operator training and clothing, and interventions in the
critical zone of the equipment including any aseptic assembly prior to the commencement of filling.”
• Hoses and delivery lines should not be too long to clean and drain.
GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994)
III. EQUIPMENT
(para 7)
[VIP ID: 3215]
“With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In some cases
manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on the floor,
thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up
or handling hoses, and possibly even placing them in transfer or batching tanks after they had been lying on the
floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may
allow moisture to collect and be a potential source of microbial contamination. Observe manufacturing areas and
operator practices, particularly when flexible hose connection are employed.”
2. Fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced
to permit cleaning.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart E -- Control of Components and Drug Product Containers and Closures
Sec. 211.80 General requirements
(c)
[VIP ID: 69]
“Bagged or boxed components of drug product containers, or closures shall be stored off the floor and suitably
spaced to permit cleaning and inspection.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
7. MATERIALS MANAGEMENT
7.4 Storage
7.41
[VIP ID: 24654]
“Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably
spaced to permit cleaning and inspection.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
7. MATERIALS MANAGEMENT
7.4 Storage
7.41
[VIP ID: 154620]
“Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably
spaced to permit cleaning and inspection.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
9. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES
9.2 Packaging Materials
9.21
[VIP ID: 24691]
“Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that
they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to
alter the quality of the intermediate or API beyond the specified limits.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.22
[VIP ID: 153990]
“Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent
contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or
other established specifications.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
9. PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES
9.2 Packaging Materials
9.21
[VIP ID: 154990]
“Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that
they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to
alter the quality of the intermediate or API beyond the specified limits.”
• Containers for filling should be clean before filling. Attention should be given to avoiding and
removing any contaminants such as glass fragments and metal particles.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 5
PRODUCTION
PACKAGING OPERATIONS
5.48
[VIP ID: 185798]
“Containers for filling should be clean before filling. Attention should be given to avoiding and removing any
contaminants such as glass fragments and metal particles.”
• Cell culture equipment and fermentation equipment should be cleaned after use.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION
18.3 Cell Culture/Fermentation
18.34
[VIP ID: 24847]
“Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should
be cleaned, and sanitized or sterilized.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION
18.4 Harvesting, Isolation and Purification
18.42
[VIP ID: 24854]
“All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching
without cleaning can be used if intermediate or API quality is not compromised.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION
18.3 Cell Culture/Fermentation
18.34
[VIP ID: 156520]
“Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should
be cleaned, and sanitized or sterilized.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION
18.4 Harvesting, Isolation and Purification
18.42
[VIP ID: 156590]
“All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching
without cleaning can be used if intermediate or API quality is not compromised.”
• If the same equipment is used for different purification steps the equipment should be appropriately
cleaned and sanitised before re-use.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION
18.5 Viral Removal/Inactivation steps
18.53
[VIP ID: 24860]
“The same equipment is not normally used for different purification steps. However, if the same equipment is to be
used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be
taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION
18.5 Viral Removal/Inactivation steps
18.53
[VIP ID: 156650]
“The same equipment is not normally used for different purification steps. However, if the same equipment is to be
used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be
taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.”
• Isolators used for aseptic processing and sterility testing should be cleaned prior to exposure to a
sporicidal process.
PI 014-2
RECOMMENDATION
ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004)
9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE
PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.
9.4
9.4.8
[VIP ID: 190534]
“The isolator should be cleaned prior to the sporicidal process. The surfaces of packaged materials and all other
items to be exposed to the sporicidal process within the isolator should be clean.
All the surfaces inside the isolator should be clean prior to exposure to the sporicidal process. Apart from removing
chemical residues that may contaminate subsequent production, the presence of deposits may enable
microorganisms to survive the process by physical shielding or neutralization of the process of inactivation. The
isolator should be designed to enable access to all surfaces for cleaning without major dismantling. Inlet and
exhaust air pathways should be designed with this in mind. If clean in place systems are used, any risks that may
arise from the presence of spray balls, drains and retained fluids should be identified and eliminated. Whichever
cleaning method is used it should result in a visibly clean dry surface free from risk of residues.”
PI 014-2
RECOMMENDATION
ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004)
7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS
SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1.
7.4
7.4.8
[VIP ID: 190476]
“The isolator should be cleaned prior to the sporicidal process. The surfaces of packaged materials and all other
items to be gassed within the isolator should be clean.”
• Containers and valves should be cleaned to ensure the absence of any contaminants such as
fabrication aids (e.g. lubricants) or undue microbiological contaminants.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 10
PRODUCTION AND QUALITY CONTROL
6
[VIP ID: 186674]
“Containers and valves should be cleaned using a validated procedure appropriate to the use of the product to
ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue microbiological
contaminants.”
• Stainless steel pipework used in the manufacturing process, connecting formulation tanks, holding
tanks and transfer lines should be sanitised prior to use.
Selected FDA 483 Observations (March 2000)
Product Manufacture
[VIP ID: 14530]
“Stainless steel pipework used in the manufacturing process, connecting formulation tanks, holding tanks and
transfer lines should be sanitized prior to use.”
• Plastic bins used to hold and store cleaned compound manufacturing equipment parts should be
washed and/or sanitised.
Selected FDA 483 Observations (November 2002)
Product Manufacture
[VIP ID: 51530]
“Plastic bins used to hold and store cleaned compound manufacturing equipment parts should be washed and / or
sanitized.”
• Stainless steel stands and metal clamps used to hold sampling apparatus and peristaltic pump
rotary pieces of equipment handled during connection of transfer tubing should be cleaned/
sanitised.
Selected FDA 483 Observations (August 2003)
Sterile Product Manufacture
[VIP ID: 53180]
“Stainless steel stands and metal clamps used to hold sampling apparatus and peristaltic pump rotary pieces of
equipment handled during connection of transfer tubing should be cleaned / sanitized.”
4. Manual cleaning of equipment rarely is a problem but procedures should be checked to ensure that
O-rings and gaskets are removed during cleaning otherwise there can be a build up of product
residues and/or dirt.
PI 007-2
RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004)
9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING
9.3 Equipment Cleaning and Sterilisation
9.3.1 Manual cleaning (see PIC/S Document PI 006, Cleaning validation) and sterilisation.
9.3.1.1
[VIP ID: 189018]
“Manual cleaning of equipment rarely is a problem but procedures should be checked to ensure that O-rings and
gaskets are removed during cleaning otherwise there can be a build up of product residues and/or dirt.”
5. Components, containers and equipment should be handled after the final cleaning process in such
a way that they are not recontaminated.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS
SANITATION
49
[VIP ID: 186096]
“Components, containers and equipment should be handled after the final cleaning process in such a way that they
are not recontaminated.”
6. Manufacturing equipment should be cleaned according to detailed and written procedures and
stored only in a clean and dry condition.
Selected FDA 483 Observations (December 2006)
Product Manufacture
[VIP ID: 194320]
“Written procedures should be established for the cleaning and maintenance of equipment, including utensils, used
in the manufacture, processing, packing or holding of a drug product.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 3
PREMISES AND EQUIPMENT
EQUIPMENT
3.36
[VIP ID: 185624]
“Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned
according to detailed and written procedures and stored only in a clean and dry condition.”
PI 008-2
PIC/S GUIDANCE DOCUMENT FOR INSPECTORS
PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
(INSPECTION GUIDE) (July 2004)
13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
13.3 EQUIPMENT
13.3.1
[VIP ID: 189284]
“Manufacturing equipment (as well as storing equipment) should be designed so that it can be easily and
thoroughly cleaned (GMP 3.36.). It should be cleaned according to detailed and written procedures and stored only
in a clean and dry condition (GMP 3.36.).”
• Processing Instructions should include the methods, or reference to the methods, to be used for
cleaning critical equipment.
EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998)
CHAPTER 4 - DOCUMENTATION
Documents required - Specifications (Manufacturing Formula and Processing Instructions)
4.15.
[VIP ID: 442]
“The Processing Instructions should include: …
b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning,
assembling, calibrating, sterilising); …”
• When necessary, written procedures should also be established for the use of suitable rodenticides,
insecticides, fungicides, fumigating agents, and cleaning and sanitising agents to prevent the
contamination of equipment.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
4. BUILDINGS AND FACILITIES
4.7 Sanitation and Maintenance
4.72
[VIP ID: 24557]
“When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides,
fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw
materials, packaging/labelling materials, intermediates, and APIs.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
4. BUILDINGS AND FACILITIES
4.7 Sanitation and Maintenance
4.72
[VIP ID: 153890]
“When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides,
fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw
materials, packaging/labelling materials, intermediates, and APIs.”
• During all phases of clinical development, including the use of small-scale facilities or laboratories to
manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that
equipment is clean.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
19. APIS FOR USE IN CLINICAL TRIALS
19.3 Equipment and Facilities
19.30
[VIP ID: 24869]
“During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture
batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean
and suitable for its intended use.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
19. APIs FOR USE IN CLINICAL TRIALS
19.3 Equipment and Facilities
19.30
[VIP ID: 156740]
“During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture
batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean
and suitable for its intended use.”
• There should be written procedures for the cleaning of the surface of bags of raw materials before
charging.
Selected FDA 483 Observations (April 2006)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 193562]
“There should be written procedures for the cleaning of the surface of bags of raw materials before charging.”
7. Before any processing or packaging operation begins, there should be recorded checks that the
equipment is clean.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 4
DOCUMENTATION
BATCH PROCESSING RECORDS
4.17
[VIP ID: 185676]
“Before any processing begins, there should be recorded checks that the equipment and work station are clear of
previous products, documents or materials not required for the planned process, and that equipment is clean and
suitable for use.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 5
PRODUCTION
PROCESSING OPERATIONS - INTERMEDIATE AND BULK PRODUCTS
5.35
[VIP ID: 185772]
“Before any processing operation is started, steps should be taken to ensure that the work area and equipment are
clean and free from any starting materials, products, product residues or documents not required for the current
operation.”
9. After cleaning, equipment should be kept clean and precautions taken not to introduce
contamination during subsequent handling.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 10 - MANUFACTURE OF PRESSURISED METERED
DOSE AEROSOL PREPARATIONS FOR INHALATION (January 1993)
Production and Quality Control
6.
[VIP ID: 1739]
“… After cleaning, valves should be kept in clean, closed containers and precautions taken not to introduce
contamination during subsequent handling, e.g. taking samples.”
10. Cleaning equipment should be stored separately and not within production or product storage
areas.
PI 008-2
PIC/S GUIDANCE DOCUMENT FOR INSPECTORS
PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
(INSPECTION GUIDE) (July 2004)
13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
13.3 EQUIPMENT
13.3.2
[VIP ID: 189286]
“…Therefore cleaning equipment should be stored separately and not within production or product storage areas.”
11. Shared (multi-product) equipment may warrant additional testing after cleaning between product
campaigns, as appropriate, to minimise the risk of cross-contamination.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION
18.3 Cell Culture/Fermentation
18.38
[VIP ID: 24851]
“Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as
appropriate, to minimize the risk of cross-contamination.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION
18.3 Cell Culture/Fermentation
18.38
[VIP ID: 156560]
“Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as
appropriate, to minimize the risk of cross-contamination.”
12. Electronic thermometers used to measure the temperature of cleaning chemicals during cleaning
should be calibrated with a reference standard which is traceable to a national/international
standard.
Selected FDA 483 Observations (May 2000)
Medical Device Manufacture
[VIP ID: 15960]
“Electronic thermometers used to measure the temperature of cleaning chemicals during cleaning should be
calibrated with a reference standard which is traceable to a national / international standard.”
13. Smoke generating equipment used for clean room qualification should be cleanable.
Selected FDA 483 Observations (March 1999)
Sterile Product Manufacture
[VIP ID: 7137]
“Smoke generating equipment used for clean room qualification should be:
2) cleanable”
14. Hand trucks used to move racks of sterilised components should be cleanable and sanitisable.
Selected FDA 483 Observations (May 1999)
Sterile Product Manufacture
[VIP ID: 7220]
“Hand trucks used to move racks of sterilized components should be cleanable and sanitizable.”
15. Flexible tubing (e.g. hoses) used in manufacturing should be hung such that they drain when not in
use.
Selected FDA 483 Observations (July 2002)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 47400]
“Hoses used for the transfer of product or waste should:
(b) correctly hung when not in use.”
16. Clean room goggles and ear protection covers should be disinfected prior to use or on a periodic
basis, and records maintained.
Selected FDA 483 Observations (January 2000)
Sterile Product Manufacture
[VIP ID: 14530]
“Clean room goggles and ear protection covers should be disinfected prior to use or on a periodic basis, and
records maintained.”
17. Equipment should be consistently cleaned in the same way it was during cleaning validation
studies.
Selected FDA 483 Observations (November 2006)
Sterile Product Manufacture
[VIP ID: 194202]
“Cleaning practices should be correlated to cleaning validations.”
18. Non dedicated transfer/storage bins should be supported by cleaning and usage records.
Selected FDA 483 Observations (June 2002)
Product Manufacture
[VIP ID: 47230]
“Non dedicated transfer / storage bins should be supported by cleaning and usage records.”
19. Piping and valves used in cleaning operations should be tagged and easily identifiable by the
operator performing the cleaning function.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
1. Equipment Design
(para 3)
[VIP ID: 1333]
“In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping
diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and
easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both
on prints and physically, have led to incorrect cleaning practices.”
5.3 Personnel
1. Personnel who perform cleaning routinely should be trained in the application of validated cleaning
procedures.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.5 Personnel
7.5.1
[VIP ID: 188674]
“Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures.
Training records should be available for all training carried out.”
• Personnel concerned with cleaning in areas where radioactive products are manufactured should
receive additional training specific to the products manufactured.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 3 - MANUFACTURE OF RADIOPHARMACEUTICALS
PERSONNEL
1
[VIP ID: 186280]
“All personnel (including those concerned with cleaning and maintenance) employed in areas where radioactive
products are manufactured should receive additional training adapted to this class of products. In particular, the
personnel should be given detailed information and appropriate training on radiation protection.”
• Personnel concerned with cleaning in areas where biological medicinal products are manufactured
should receive additional training specific to the products manufactured.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL
PRODUCTS FOR HUMAN USE (January 1993)
Personnel
1.
[VIP ID: 1514]
“All personnel (including those concerned with cleaning, maintenance or quality control) employed in areas where
biological medicinal products are manufactured should receive additional training specific to the products
manufactured and to their work. Personnel should be given relevant information and training in hygiene and
microbiology.”
• Personnel concerned with cleaning in areas where sterile products products are manufactured
should receive additional training specific to the products manufactured. This training should
include reference to hygiene and to the basic elements of microbiology.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS
PERSONNEL
14
[VIP ID: 186026]
“All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive
regular training in disciplines relevant to the correct manufacture of sterile products, including reference to hygiene
and to the basic elements of microbiology.”
2. Cleaning personnel training records should be available for all training carried out.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.5 Personnel
7.5.1
[VIP ID: 188674]
“Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures.
Training records should be available for all training carried out.”
3. Personnel carrying out manual cleaning procedures should be supervised at regular intervals.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.5 Personnel
7.5.2
[VIP ID: 188676]
“It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out
manual cleaning procedures should be supervised at regular intervals.”
4. High standards of personal hygiene and cleanliness are essential for personnel involved in the
cleaning of sterile preparations.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL
PRODUCTS (September 2003)
Personnel
16
[VIP ID: 63030]
“High standards of personal hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile
preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or
types of contaminants; periodic health checks for such conditions are desirable.”
5. There should be a training tracking system to ensure that only trained personnel perform cleaning
tasks.
Selected FDA 483 Observations (September 1999)
Product Manufacture
[VIP ID: 8320]
“Production operator training should:
(1) include a training tracking system to ensure that only trained personnel perform assigned tasks”
6. Where contract cleaners are used in clean rooms their gowning protocols and personnel practices
should be formally audited.
Selected FDA 483 Observations (July 1998)
Medical Device Manufacture
[VIP ID: 6763]
“Where contract cleaners are used in clean rooms their gowning protocols and personnel practices should be
formally audited.”
1. Certain materials can be stored outdoors in suitable containers, provided the containers are
appropriately cleaned before opening and use.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
7. MATERIALS MANAGEMENT
7.4 Storage
7.43
[VIP ID: 24656]
“Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and
containers are appropriately cleaned before opening and use.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
7. MATERIALS MANAGEMENT
7.4 Storage
7.43
[VIP ID: 154640]
“Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and
containers are appropriately cleaned before opening and use.”
2. If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-
contamination from the tanker.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
7. MATERIALS MANAGEMENT
7.2 Receipt and Quarantine
7.22
[VIP ID: 24644]
“If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination from
the tanker. Means of providing this assurance could include one or more of the following:
(a) certificate of cleaning
(b) testing for trace impurities
(c) audit of the supplier.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
7. MATERIALS MANAGEMENT
7.2 Receipt and Quarantine
7.22
[VIP ID: 154520]
“If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination from
the tanker. Means of providing this assurance could include one or more of the following:
- certificate of cleaning
- testing for trace impurities
- audit of the supplier.”
(3) "rinse or wipe with a small amount of acetone or alcohol solvent until there is no presence of dye and / or odor of
liquid or solution"
(4) "rinse with hot water until completely free from soap"
(5) "repeat cleaning procedure if necessary”
2. include a list of which personnel are trained and responsible for the cleaning of specific equipment.
Selected FDA 483 Observations (January 2007)
Packaging & Labelling
[VIP ID: 194404]
“Written procedures for cleaning and maintenance should include assignment of responsibility, description in
sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper
cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall
include, but are not necessarily limited to, the following:
(1) Assignment of responsibility for cleaning and maintaining equipment;”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP)
DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT
C. Equipment
1. Production Equipment
para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the
following issues, where applicable:
- Assignment of responsibility and frequency for cleaning and maintenance of equipment”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.21
[VIP ID: 24566]
“Written procedures should be established for cleaning of equipment and its subsequent release for use in the
manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to
clean each type of equipment in a reproducible and effective manner. These procedures should include:
(1) Assignment of responsibility for cleaning of equipment;”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.21
[VIP ID: 153980]
“Written procedures should be established for cleaning of equipment and its subsequent release for use in the
manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to
clean each type of equipment in a reproducible and effective manner. These procedures should include:
- Assignment of responsibility for cleaning of equipment;”
3. include a description in sufficient detail of the methods, equipment, and materials used in cleaning
the buildings and facilities, and the methods of disassembling and reassembling equipment as
necessary to assure proper cleaning.
Selected FDA 483 Observations (January 2007)
Packaging & Labelling
[VIP ID: 194404]
“Written procedures for cleaning and maintenance should include assignment of responsibility, description in
sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper
cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart C -- Buildings and Facilities
Sec. 211.56 Sanitation
(b)
[VIP ID: 48]
“There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the
cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such
written procedures shall be followed.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart C -- Buildings and Facilities
Sec. 211.56 Sanitation
(c)
[VIP ID: 49]
“There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and
cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of
equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and
shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered and used in
accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall
include, but are not necessarily limited to, the following:
(3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance
operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning
and maintenance;”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP)
DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT
C. Equipment
1. Production Equipment
para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the
following issues, where applicable:
- Description of cleaning and maintenance procedures in sufficient detail to include disassembly and reassembly of
equipment”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.4
[VIP ID: 188668]
“The cleaning process should be documented in an SOP.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.72
[VIP ID: 24771]
“The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable
cleaning levels, parameters to be monitored and controlled, and analytical methods.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.72
[VIP ID: 155760]
“The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable
cleaning levels, parameters to be monitored and controlled, and analytical methods.”
4. consider non-contact parts into which product may migrate (e.g. premises, seals, flanges, mixing
shaft, fans of ovens, heating elements etc.).
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION
38
[VIP ID: 187106]
“Normally only cleaning procedures for product contact surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning and
reuse should be validated. Cleaning intervals and methods should be determined.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.1
[VIP ID: 188640]
“Normally only cleaning procedures for product contact surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges,
mixing shaft, fans of ovens, heating elements etc.”
• Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require
cleaning of the units.
Selected FDA 483 Observations (September 2002)
Sterile Product Manufacture
[VIP ID: 47810]
“Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units.”
6. include the between use cleaning of columns used in HPLC testing of drug formulations.
Selected FDA 483 Observations (July 1999)
Laboratories
[VIP ID: 7500]
“There should be written procedures documenting the between use cleaning of columns used in HPLC testing of
drug formulations.”
7. require that a major cleaning be executed between lots of products obtained from an approved drug
substance supplier and a non-approved supplier.
Selected FDA 483 Observations (January 2004)
Product Manufacture
[VIP ID: 71120]
“Equipment cleaning SOPs for production lines should require that a major cleaning be executed between lots of
products obtained from an approved drug substance supplier and a non-approved supplier, to prevent cross-
contamination of impurities that may be present in the different drug sources.”
8. define different procedures as required, for multi-use equipment cleaning, depending on what
product or intermediate was last produced.
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994)
PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(a) Multipurpose Equipment
(para 1)
[VIP ID: 3434]
“…The cleaning program should take into consideration the need for different procedures depending on what
product or intermediate was produced.”
9. include diagrams and identify specific valves for clean-in-place (CIP) systems.
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994)
PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(e) Cleaning of Product Contact Surfaces
(para 3)
[VIP ID: 3444]
“Specific inspectional coverage for cleaning should include:
1. Detailed Cleaning Procedure:
There should be a written equipment cleaning procedure that provides details of what should be done and materials
to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate. For stationary vessels,
often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be
necessary, along with identification of specific valves.”
11. provide instructions for the cleaning and storage of sampling equipment.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 6
QUALITY CONTROL
SAMPLING
6.11
[VIP ID: 185856]
“The sample taking should be done in accordance with approved written procedures that describe:
- instructions for the cleaning and storage of sampling equipment.”
12. include the method for protection of clean equipment from contamination prior to use.
Selected FDA 483 Observations (January 2007)
Packaging & Labelling
[VIP ID: 194404]
“Written procedures for cleaning and maintenance should include assignment of responsibility, description in
sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper
cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall
include, but are not necessarily limited to, the following:
(5) Protection of clean equipment from contamination prior to use;”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP)
DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT
C. Equipment
1. Production Equipment
para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the
following issues, where applicable:
- Protection of clean equipment from contamination prior to use”
13. include directions for the use of cleaning and disinfecting agents.
PI 012-2
RECOMMENDATION ON
STERILITY TESTING (July 2004)
9. CLEANING, SANITISATION AND DISINFECTION
9.5
[VIP ID: 190292]
“Records should be retained in respect of routine preparation of cleaning and disinfecting agents, directions for
their use, and validation of their efficacy.”
• Specifying which cleaning agent(s) will be used and at what concentration(s) (to include the
cleaning of floors and table tops in processing areas).
Extracted from FDA Warning Letter 2003-NOL-01 (October 2002)
USA
10/10/2002
[VIP ID: 49860]
“Written procedures are not established for the use of suitable cleaning and sanitizing agents designed to prevent
the contamination of equipment, drug product containers, closures and packaging, or labeling materials [21 CFR
211.56(c)];”
14. require the rotation of sanitising agents (disinfectants) used in aseptic processing areas and
surrounding clean rooms.
Selected FDA 483 Observations (October 1997)
Sterile Product Manufacture
[VIP ID: 2486]
“Sanitizing agents (disinfectants) used in the aseptic processing areas and the surrounding clean rooms should be
rotated.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
9. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES
9.2 Packaging Materials
9.22
[VIP ID: 24692]
“If containers are re-used, they should be cleaned in accordance with documented procedures and all previous
labels should be removed or defaced.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
9. PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES
9.2 Packaging Materials
9.22
[VIP ID: 155000]
“If containers are re-used, they should be cleaned in accordance with documented procedures and all previous
labels should be removed or defaced.”
16. include specific instructions to ensure that repeat samples are not taken from identical locations.
Selected FDA 483 Observations (October 1998)
Product Manufacture
[VIP ID: 6843]
“Cleaning swab sample procedures should ensure that repeat samples are not taken from identical locations.”
• include specific instructions to ensure that micro and chemical samples are not collected from the
same areas.
Selected FDA 483 Observations (February 1997)
Product Manufacture
[VIP ID: 2470]
“Cleaning validation protocols / SOPs should include specific instructions to ensure that microbiological and
chemical samples are not collected from the same areas.”
17. include the requirement to clean product contact equipment following maintenance operations.
Selected FDA 483 Observations (June 1998)
Product Manufacture
[VIP ID: 6715]
“Cleaning should be performed after product contact equipment maintenance in accordance with a written
procedure.”
• Cleaning rinse times should specify if they are for individual pieces of equipment or for rinsing
equipment together.
Selected FDA 483 Observations (November 2006)
Sterile Product Manufacture
[VIP ID: 194204]
“Cleaning rinse times should specify if they are for individual pieces of equipment or for rinsing equipment
together.”
20. state the number of consecutive lots which can be manufactured without major cleaning.
Selected FDA 483 Observations (February 2005)
Product Manufacture
[VIP ID: 138130]
“Equipment cleaning, maintenance and sanitation procedures should:
b. Explain the frequency for the cleaning procedure.”
21. ensure that residual water is not left in equipment (such as pumps, tri-blenders, pipework and tanks
etc.) following cleaning.
HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003)
2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations)
2.1 PREMISES - C.02.004
2.1.4
[VIP ID: 65620]
“WHAT IS THE ACCEPTABLE LIMIT FOR DEW POINT OF THE COMPRESSED AIR USED IN PNEUMATIC
EQUIPMENT AND TO DRY THE MANUFACTURING TANKS AFTER CLEANING?
…Similarly, it is important to make sure that residual water has been completely eliminated from hard to reach
surfaces of the equipment after cleaning operations.”
23. include provisions for controlling access to cleaning equipment (including mops and washing
buckets) used in clean/packaging rooms.
Selected FDA 483 Observations (May 2000)
Medical Device Manufacture
[VIP ID: 15980]
“Access to cleaning equipment including mops and washing buckets used in clean / packaging rooms should be
controlled.”
24. require the status (clean/dirty) of the equipment (including utensils and spare parts used in the
manufacturing area) to be clearly identified.
Selected FDA 483 Observations (May 2005)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 177290]
“Utensils for API repackaging operations, which are stored as clean, should be identified as cleaned and there
should be documentation to assure these utensils are clean.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.26
[VIP ID: 24571]
“Equipment should be identified as to its contents and its cleanliness status by appropriate means.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.26
[VIP ID: 154030]
“Equipment should be identified as to its contents and its cleanliness status by appropriate means.”
• Flexible tubing (e.g. hoses) used in manufacturing should carry distinctive identification to track its
use and cleaning.
Selected FDA 483 Observations (July 2002)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 47400]
“Hoses used for the transfer of product or waste should:
(a) be identified to indicate the cleaning status.”
25. include periodic testing to assure that the surface has been cleaned to the validated level.
Selected FDA 483 Observations (January 1999)
Sterile Product Manufacture
[VIP ID: 7106]
“Manufacturing equipment and parts should be periodically tested for product/cleaning/sanitizing residues.”
26. require the dedication of equipment that contains tarry or gummy residues, that cannot be removed
readily, for use only with limited portions of a synthesis.
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.6 Equipment
7.6.2
[VIP ID: 188680]
“Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in
the bulk manufacturing)…”
27. require the dedication of equipment for products with a high safety risk (e.g. biologicals or products
of high potency which may be difficult to detect below an acceptable limit).
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.6 Equipment
7.6.2
[VIP ID: 188680]
“Dedicated equipment should be used … for products with a high safety risk (e.g. biologicals or products of high
potency which may be difficult to detect below an acceptable limit).”
28. include the definition of cleaning schedules, including, where appropriate, sanitising schedules.
Selected FDA 483 Observations (December 2006)
Product Manufacture
[VIP ID: 194320]
“… Routine maintenance schedules and procedures should be established for equipment such as an oscillating
granulator used in the production of powder products and this should include the care, cleaning, and maintenance
of the mesh screen to prevent the formation of holes.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(a)
[VIP ID: 55]
“Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions
or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the
official or other established requirements.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall
include, but are not necessarily limited to, the following:
(2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;”
Sanitation
37.
[VIP ID: 1450]
“The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a
written programme.”
29. consider the different physical properties and impurity profiles of raw materials sourced from
different suppliers, since the raw materials may behave differently.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.7
[VIP ID: 188652]
“Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such
differences should be considered when designing cleaning procedures, as the materials may behave differently.”
30. consider the existence of conditions favourable to reproduction of micro organisms (e.g. moisture,
temperature, crevices and rough surfaces) and the time of storage.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.7 Microbiological Aspects
7.7.1
[VIP ID: 188682]
“The existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices
and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive
microbial contamination.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.7 Microbiological Aspects
7.7.2
[VIP ID: 188684]
“The period and when appropriate, conditions of storage of equipment before cleaning and the time between
cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide
confidence that routine cleaning and storage of equipment does not allow microbial proliferation.”
NOTE: The EC states that, generally, in the case of batch-to-batch production, it is not necessary to
clean after each batch. However, cleaning intervals and methods should be determined.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.3
[VIP ID: 188644]
“Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning
intervals and methods should be determined.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE
SUBSTANCES USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.23
[VIP ID: 24568]
“Where equipment is assigned to continuous production or campaign production of successive batches of the
same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-
over of contaminants (e.g. degradants or objectionable levels of micro-organisms).”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE
SUBSTANCES USED AS STARTING MATERIALS (October 2005)
8. PRODUCTION AND IN-PROCESS CONTROLS
8.5 Contamination Control
8.50
[VIP ID: 24684]
“Residual materials can be carried over into successive batches of the same intermediate or API if there is
adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals
remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing
vessel upon transfer of the material to the next step in the process. Such carryover should not result in the
carryover of degradants or microbial contamination that may adversely alter the established API impurity
profile.”
32. include the method of inspection of the cleaned equipment prior to use.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall
include, but are not necessarily limited to, the following:
(6) Inspection of equipment for cleanliness immediately before use.”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP)
DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT
C. Equipment
1. Production Equipment
para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the
following issues, where applicable:
- Inspection of equipment and calibration, if indicated, prior to use”
• include specific criteria for the cleaning evaluation of manufacturing equipment during visual
inspection before product manufacture.
Selected FDA 483 Observations (November 2003)
Product Manufacture
[VIP ID: 72300]
“Cleaning Validation Protocols should include:
d. Specific criteria for the cleaning evaluation of manufacturing equipment during visual inspection before product
manufacture.”
34. address how to clean dirty plastic and stainless steel containers that had previously contained
weighed out components.
Selected FDA 483 Observations (January 2002)
Product Manufacture
[VIP ID: 46270]
“Standard Operating Procedures for compounding washing areas should address how to clean dirty plastic and
stainless steel containers that had previously contained weighed out components.”
37. address the control of cleaning labels where they comprise the sole documentation and verification
for cleaning operations.
Selected FDA 483 Observations (February 2005)
Product Manufacture
[VIP ID: 138120]
“There should be procedures for the control of cleaning labels, where they comprise the sole documentation and
verification for cleaning operations.”
39. include the cleaning of the surface of bags of raw materials before charging.
Selected FDA 483 Observations (April 2006)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 193562]
“There should be written procedures for the cleaning of the surface of bags of raw materials before charging.”
40. be collected and collated, or developed in draft documentation form from equipment supplier
specifications and operating procedures as part of the Installation Qualification activity.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and
Operational Qualification of equipment involved in the manufacture of pharmaceutical products.
5.2 Installation Qualification (l.Q.) - Overview Statement
5.2.2
[VIP ID: 188524]
“Identification and documenting of maintenance requirements for each installed item and the collection and
collation of supplier operating and working instructions, maintenance and cleaning requirements, should form the
minimum documentation for a satisfactory Installation Qualification.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and
Operational Qualification of equipment involved in the manufacture of pharmaceutical products.
5.3 Installation Qualification - Essential Elements - Installation Qualification
5.3.7
[VIP ID: 188538]
“At the Installation Qualification stage the company should document preventative maintenance requirements for
installed equipment. At this stage new equipment and the preventative maintenance requirements should be added
to the preventative maintenance schedule of the pharmaceutical manufacturer.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and
Operational Qualification of equipment involved in the manufacture of pharmaceutical products.
5.3 Installation Qualification - Essential Elements - Installation Qualification
5.3.7
[VIP ID: 188538]
“…The draft cleaning documentation should be finalised following experience and observation at the Operational
Qualification stage and then verified at the Performance Qualification stage.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and
Operational Qualification of equipment involved in the manufacture of pharmaceutical products.
5.5 Operational Qualification - Essential Elements
5.5.4
[VIP ID: 188554]
“Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory
Operational Qualification exercise and issued as standard operating procedures (SOPs).”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and
Operational Qualification of equipment involved in the manufacture of pharmaceutical products.
5.5 Operational Qualification - Essential Elements
5.5.4
[VIP ID: 188554]
“Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory
Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these
procedures should be validated as part of the Performance Qualification phase.”
1. address the ends of the ribbon blender where the horizontal bar enters the unit.
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)
B. Post-Approval Prospective Validation Inspections
2. Manufacturing Procedures and Equipment
a. Blenders - 2. Ribbon Blender (para 4)
[VIP ID: 3125]
“Cleaning problems, particularly at the ends of the ribbon blender where the horizontal bar enters the blender, have
been identified.”
2. require the disassembly and cleaning of seals/packing between batches of different products.
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)
B. Post-Approval Prospective Validation Inspections
2. Manufacturing Procedures and Equipment
a. Blenders - 2. Ribbon Blender (para 4)
[VIP ID: 3125]
“…If manufacturers do not disassemble and clean the seals/packing between batches, they should have data to
demonstrate the absence of foreign contaminants between batches of different products processed in the blender.”
• If not, data should be developed to demonstrate the absence of foreign contaminants between
batches of different products.
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)
B. Post-Approval Prospective Validation Inspections
2. Manufacturing Procedures and Equipment
a. Blenders - 2. Ribbon Blender (para 4)
[VIP ID: 3125]
“…If manufacturers do not disassemble and clean the seals/packing between batches, they should have data to
demonstrate the absence of foreign contaminants between batches of different products processed in the blender.”
1. require the disassembly and cleaning of the intensifier bar between products.
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)
B. Post-Approval Prospective Validation Inspections
2. Manufacturing Procedures and Equipment
a. Blenders - 4. High Shear (high energy) Mixers (para 4)
[VIP ID: 3131]
“…Also, cleaning of the blender requires disassembly of the intensifier bar between products.”
• The intensifier bar in the centre of the blender rotates at very high speeds to break down smaller,
harder agglomerates. The extremely high speed of the intensifier bar generates considerable heat
that can sometimes result in charring of some sugar base granulations.
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)
B. Post-Approval Prospective Validation Inspections
2. Manufacturing Procedures and Equipment
a. Blenders - 4. High Shear (high energy) Mixers (para 4)
[VIP ID: 3131]
“The presence of an intensifier bar in the center of the blender which rotates at very high speeds breaks down
smaller, harder agglomerates. A major disadvantage of this type of blender is that the extremely high speed of the
intensifier bar generates considerable heat that can sometimes result in charring of some sugar base granulations.”
• The same comments are applicable to other high energy mixers which also rely on high speed
choppers to disperse powders.
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)
B. Post-Approval Prospective Validation Inspections
2. Manufacturing Procedures and Equipment
a. Blenders - 4. High Shear (high energy) Mixers (para 4)
[VIP ID: 3131]
“…It should be pointed out that these same comments are applicable to other high energy mixers which also rely on
high speed choppers to disperse powders.”
1. require dryer bags, which are difficult to clean, to be dedicated to a specific product.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
III. General Requirements
(para 1)
[VIP ID: 1323]
“…Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a
specific product.”
The following points should be considered when developing cleaning record packages:
There were no equipment cleaning records for several of the product contact, multi-use formulation mixing rods.
The investigators observed that there was no evidence to demonstrate that the mixing rods were dedicated to
specific products.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
QUALIFICATION
Qualification of established (in-use) facilities, systems and equipment
19
[VIP ID: 187068]
“Evidence should be available to support and verify the operating parameters and limits for the critical variables of
the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures
and operator training procedures and records should be documented.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance
(c)
[VIP ID: 63]
“Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in §§ 211.180 and 211.182.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
6. DOCUMENTATION AND RECORDS
6.2 Equipment Cleaning and Use Record
6.20
[VIP ID: 24597]
“Records of major equipment use, cleaning, sanitization and / or sterilization and maintenance should show the
date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person
who performed the cleaning and maintenance.”
2. The amount of documentation necessary for executing various cleaning steps or procedures will
vary depending upon the complexity of the system and cleaning process and the ability and training
of operators.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
2. Cleaning Process Written Procedure and Documentation
(para 1)
[VIP ID: 1337]
“Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of
documentation required. We have seen general SOPs, while others use a batch record or log sheet system that
requires some type of specific documentation for performing each step. Depending upon the complexity of the
system and cleaning process and the ability and training of operators, the amount of documentation necessary for
executing various cleaning steps or procedures will vary.”
• For relatively simple cleaning operations, the mere documentation that the overall cleaning process
was performed might be sufficient.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
2. Cleaning Process Written Procedure and Documentation
(para 2)
[VIP ID: 1338]
“…for relatively simple cleaning operations, the mere documentation that the overall cleaning process was
performed might be sufficient.”
• When more complex cleaning procedures are required, it is important to document the critical
cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific
documentation on the equipment itself, which includes information about who cleaned it and when,
is valuable.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
2. Cleaning Process Written Procedure and Documentation
(para 2)
[VIP ID: 1338]
“When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for
example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself
which includes information about who cleaned it and when is valuable.”
• Other factors such as history of cleaning, residue levels found after cleaning, and variability of test
results may also dictate the amount of documentation required. For example, when variable residue
levels are detected following cleaning, particularly for a process that is believed to be acceptable,
one must establish the effectiveness of the process and operator performance.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
2. Cleaning Process Written Procedure and Documentation
(para 3)
[VIP ID: 1339]
“Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may
also dictate the amount of documentation required. For example, when variable residue levels are detected
following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness
of the process and operator performance. Appropriate evaluations must be made and when operator performance is
deemed a problem, more extensive documentation (guidance) and training may be required.”
• Appropriate evaluations must be made and, when operator performance is deemed a problem,
more extensive documentation (guidance) and training may be required.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
2. Cleaning Process Written Procedure and Documentation
(para 3)
[VIP ID: 1339]
“…Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive
documentation (guidance) and training may be required.”
3. When the equipment is dedicated to the manufacture of a single product, and provided that lots or
batches of such product follow in numerical order and are manufactured in numerical sequence,
cleaning can be recorded as part of the batch records.
Extracted from FDA warning letter MIN 06-30 (July 2006)
USA
27-Jul-06
8
[VIP ID: 192336]
“The batch records lack records of the cleaning for dedicated equipment [21 CFR 211.182].”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart J -- Records and Reports
Sec. 211.182 Equipment cleaning and use log
[VIP ID: 223]
“…If equipment is dedicated to manufacture of one product, then individual equipment logs are not required,
provided that lots or batches of such product follow in numerical order and are manufactured in numerical
sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be
part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and
sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
6. DOCUMENTATION AND RECORDS
6.2 Equipment Cleaning and Use Record
6.21
[VIP ID: 24598]
“If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not
necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is
employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
6. DOCUMENTATION AND RECORDS
6.2 Equipment Cleaning and Use Record
6.21
[VIP ID: 154300]
“If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not
necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is
employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.”
4. When the equipment is not dedicated to the manufacture of a single product, cleaning should be
recorded in individual equipment logs.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
CHAPTER 4
DOCUMENTATION
PROCEDURES AND RECORDS - Other
4.28
[VIP ID: 185698]
“Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations,
maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations
out.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart J -- Records and Reports
Sec. 211.182 Equipment cleaning and use log
[VIP ID: 223]
“A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and
adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot
number of each batch processed.”
PI 008-2
PIC/S GUIDANCE DOCUMENT FOR INSPECTORS
PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
(INSPECTION GUIDE) (July 2004)
13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES
13.13 DOCUMENTATION
13.13.18
[VIP ID: 189578]
“Log books should be kept for major or critical equipment recording (GMP 4.28), e.g. plasmapheresis machines,
microhematocrit centrifuges, scales etc. and contain information about any validation, calibration, maintenance,
cleaning or repair operations, including the dates and identity of people who carried out these operations (GMP
4.28.). They should also contain the approval of return to use after validation and planned maintenance (GMP-s 36)
as well after major repairs.”
• Equipment cleaning logs should be maintained for trailers, rail cars, and storage tanks, especially
those installed at a health care facility or a hospital.
GUIDANCE FOR INDUSTRY
CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICAL GASES (May 2003)
XI. RECORDS AND REPORTS
B. Equipment Cleaning and Use Log
para 3
[VIP ID: 181030]
“Equipment cleaning and use logs can be maintained for trailers, rail cars, and storage tanks, especially those
installed at a health care facility or a hospital.”
5. Where equipment logs are used, the persons performing and double-checking the cleaning shall
date and sign or initial them to indicate that the work was performed. Entries in the log shall be in
chronological order. Such Logs should be accurate and complete.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart J -- Records and Reports
Sec. 211.182 Equipment cleaning and use log
[VIP ID: 223]
“…The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log
indicating that the work was performed. Entries in the log shall be in chronological order.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
6. DOCUMENTATION AND RECORDS
6.2 Equipment Cleaning and Use Record
6.20
[VIP ID: 24597]
“Records of major equipment use, cleaning, sanitization and / or sterilization and maintenance should show the
date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person
who performed the cleaning and maintenance.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
6. DOCUMENTATION AND RECORDS
6.2 Equipment Cleaning and Use Record
6.20
[VIP ID: 154290]
“Records of major equipment use, cleaning, sanitization and/or sterilization and maintenance should show the date,
time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who
performed the cleaning and maintenance.”
• The cleaning record should be signed by the operator who performed the cleaning and by the
person responsible for Production and should be reviewed by Quality Assurance.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.6
[VIP ID: 188672]
“The cleaning record should be signed by the operator who performed the cleaning and by the person responsible
for Production and should be reviewed by Quality Assurance.”
• Equipment cleaning batch records should document the completion of times, steps of equipment
cleaning and completion of room cleaning.
Selected FDA 483 Observations (February 2001)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 26920]
“Equipment cleaning batch records should document the completion of times, steps of equipment cleaning and
completion of room cleaning.”
6. Filling rooms should have dedicated daily logs for sanitisation and cleaning.
Selected FDA 483 Observations (August 1999)
Sterile Product Manufacture
[VIP ID: 7770]
“Filling rooms should:
(3) have dedicated daily logs for sanitization and cleaning”
7. There should be records of equipment cleaning prior to sterilisation (e.g. nozzles, tubing and
hoses).
Selected FDA 483 Observations (December 2005)
Sterile Product Manufacture
[VIP ID: 180110]
“There should be records of cleaning and wrapping of all equipment prior to sterilisation, e.g. nozzles, tubing and
hoses.”
• Cleaning records should record the time equipment is cleaned in order to determine the time period
between cleaning/wrapping and sterilisation.
Selected FDA 483 Observations (December 2005)
Sterile Product Manufacture
[VIP ID: 180120]
“Cleaning records should record the time equipment is cleaned and wrapped in order to determine the time period
between cleaning/wrapping and sterilisation.”
9. Records should be kept of cleaning performed in such a way that the following information is readily
available:
(a) the area or piece of equipment cleaned
(b) the person who carried out the cleaning
(c) when the cleaning was carried out
(d) the SOP defining the cleaning process
(e) the product which was previously processed on the equipment being cleaned.
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.5
[VIP ID: 188670]
“Records should be kept of cleaning performed in such a way that the following information is readily available:
- the area or piece of equipment cleaned,
- the person who carried out the cleaning,
- when the cleaning was carried out,
- the SOP defining the cleaning process,
- the product which was previously processed on the equipment being cleaned.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
6. DOCUMENTATION AND RECORDS
6.2 Equipment Cleaning and Use Record
6.20
[VIP ID: 24597]
“Records of major equipment use, cleaning, sanitization and / or sterilization and maintenance should show the
date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person
who performed the cleaning and maintenance.”
10. Records should be kept of the routine preparation of cleaning and disinfecting agents.
PI 012-2
RECOMMENDATION ON
STERILITY TESTING (July 2004)
9. CLEANING, SANITISATION AND DISINFECTION
9.5
[VIP ID: 190292]
“Records should be retained in respect of routine preparation of cleaning and disinfecting agents, directions for
their use, and validation of their efficacy.”
12. There should be a record to document the cleaning and sanitisation of goggles worn by personnel
in the classified areas.
Selected FDA 483 Observations (December 2006)
Sterile Product Manufacture
[VIP ID: 194292]
“There should be a record to document cleaning or sanitization of the goggles that are worn by personnel while in
the Class 100 and Class 10,000 areas.”
13. Cleaning records should include a description of the cleaning method(s) used and identify what was
actually cleaned and what cleaning agents were used to perform the cleaning operations.
Selected FDA 483 Observations (December 2006)
Product Manufacture
[VIP ID: 194288]
“… There should be documentation of which cleaning procedures were actually followed, such as recording of
times and water temperatures, and some indication that those involved in the cleaning had read the protocol and/or
the cleaning procedures.”
14. There should be records documenting the cleaning of bins, which are used for the storage of
powders and blends and the gravity feed delivery of powders and blends to encapsulation and
tableting equipment, and also used for the storage, and transfer of bulk tablets and capsules and
the delivery of bulk tablets and capsules to bottle filling lines.
Selected FDA 483 Observations (March 2006)
Product Manufacture
[VIP ID: 193192]
“There should be records documenting the usage and cleaning of bins, which are used for the storage of powders
and blends and the gravity feed delivery of powders and blends to encapsulation and tableting equipment, and also
used for the storage, and transfer of bulk tablets and capsules and the delivery of bulk tablets and capsules to bottle
filling lines.”
1. be specific for the substance to be assayed and provide a sensitivity that reflects the level of
cleanliness determined to be acceptable by the company.
Selected FDA 483 Observations (December 2006)
Product Manufacture
[VIP ID: 194324]
“Cleaning validation, for equipment, which is not dedicated to one product, should include the evaluation of
microbiological control, a recovery study performed to demonstrate the sensitivity and specificity (detection limit) of
analytical equipment to demonstrate that residual product is removed after cleaning, documentation of the sampling
method or location used in the cleaning validation and the establishment of time limitation of cleaning prior to next
use.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION
37
[VIP ID: 187104]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection
limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the
residue or contaminant.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.10 Analytical Methods
7.10.2
[VIP ID: 188698]
“The analytical methods used to detect residuals or contaminants should be specific for the substance to be
assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.74
[VIP ID: 24773]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection
limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the
residue or contaminant. The method's attainable recovery level should be established. Residue limits should be
practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the
minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious
component.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.74
[VIP ID: 155780]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection
limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the
residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be
practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the
minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious
component.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.74
[VIP ID: 155780]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection
limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the
residue or contaminant. The method’s attainable recovery level should be established.”
4. define system suitability linearity requirements for test methods utilising standard curves.
Selected FDA 483 Observations (April 2000)
Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(3) system suitability linearity requirements for test methods utilizing standard curves”
5. include the requirement for printing standard curves when the instrument has the capability.
Selected FDA 483 Observations (April 2000)
Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(4) printing out of standard curves where the instrument has the capability”
6. include tests to show the precision (reproducibility) of the instrument at the time of use.
Selected FDA 483 Observations (April 2000)
Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(5) tests to show the precision (reproducibility) of the instrument at the time of use”
8. include a statement that cleaning swab samples should not be composited prior to analysis.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April
2006)
Subpart E -- Control of Components and Drug Product Containers and Closures
Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures
(c)
[VIP ID: 75]
“Samples shall be collected in accordance with the following procedures:
(4) If it is necessary to sample a component from the top, middle, and bottom of its container, such sample
subdivisions shall not be composited for testing.”
10. include the formula used to calculate the amount of possible contamination based on analysis.
Selected FDA 483 Observations (October 1997)
Product Manufacture
[VIP ID: 2480]
“The procedure for the collection of rinse water samples should take into account:
5. formula used to calculate the amount of possible contamination based on analysis”
1. Test method results should be reported with reference to the limit of detection of the analytical
equipment. i.e. "less than the detection limit" rather than 0.0.
Selected FDA 483 Observations (November 1997)
Laboratories
[VIP ID: 6242]
“Test method results should be reported with reference to the limit of detection of the analytical equipment.
i.e. "less than the detection limit" rather than 0.0.”
In addition to the more specific points for consideration generated as part of the review the following
general notes were also compiled:
1. Sanitation procedures shall apply to work performed by contractors or temporary employees as well
as work performed by full-time employees during the ordinary course of operations.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April,
2003)
Subpart C - Buildings and Facilities
21 CFR 211.56 (d)
“Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work
performed by full-time employees during the ordinary course of operations.”
2. Environmental monitoring should include monitoring of the sanitisation fluid container used by
operators to sanitise gloved hands and surfaces during the aseptic filling of products.
Selected FDA 483 Observations (July 1998)
Sterile Product Manufacture
[VIP ID: 6297]
“Environmental monitoring should include monitoring of the sanitization fluid container used by operators to
sanitize gloved hands and surfaces during the aseptic filling of products.”
3. Where non-disposal gloves are used during the weighing of more than one material, they should be
routinely cleaned following the weighing of each material.
Selected FDA 483 Observations (April 1998)
Product Manufacture
[VIP ID: 6389]
“Where non-disposal gloves are used during the weighing of more than one material, they should be routinely
cleaned following the weighing of each material.”
4. Disinfectants and detergents dilutions should be kept in previously cleaned containers and should
only be stored for defined periods unless sterilised.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS
SANITATION
38
[VIP ID: 186074]
“Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in
previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and
detergents used in Grades A and B areas should be sterile prior to use.”
PI 007-2
RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004)
9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING
9.4 Disinfection
9.4.1
[VIP ID: 189032]
“There should be documented procedures describing the preparation and storage of disinfectants and detergents.
These agents should be monitored for microbial contamination; dilutions should be kept in previously cleaned
containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in
Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being
filled and have a short in-use shelf life.”
• Sterile filtered disinfectants and sanitising agents used in an aseptic core should be periodically
monitored.
PI 007-2
RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004)
9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING
9.4 Disinfection
9.4.1
[VIP ID: 189032]
“…Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are
used they should be sterile before being filled and have a short in-use shelf life.”
5. Disinfectants and sanitising agents should be sterile filtered prior to introduction into an aseptic
core.
Selected FDA 483 Observations (April 1998)
Sterile Product Manufacture
[VIP ID: 6348]
“Disinfectants and sanitizing agents should be sterile filtered prior to introduction into an aseptic core.”
• Strains of factory isolates from firms controlled environments should be used in the evaluation of
sanitising solutions.
Selected FDA 483 Observations (April 1999)
Sterile Product Manufacture
[VIP ID: 7177]
“Strains of factory isolates from firms controlled environments should be used in the evaluation of sanitizing
solutions.”
• Monitoring of clean areas should be undertaken regularly in order to detect the development of
resistant strains.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL
PRODUCTS (September 2003)
Sanitation
37
[VIP ID: 63300]
“... Monitoring should be undertaken regularly in order to detect the development of resistant strains.”
7. All concentrations of disinfectants should be evaluated for detrimental effects on the microbial
growth media used.
Selected FDA 483 Observations (July 1998)
Sterile Product Manufacture
[VIP ID: 6759]
“All concentrations of disinfectants should be evaluated for detrimental effects on the microbial growth media
used.”
9. Where disinfectants are used in clean areas, more than one type should be employed.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL
PRODUCTS (September 2003)
Sanitation
37
[VIP ID: 63300]
“... Where disinfectants are used, more than one type should be employed. ...”
10. Carts used to transport partially stoppered vials should be sanitised and monitored for viable
contamination.
Selected FDA 483 Observations (May 1999)
Sterile Product Manufacture
[VIP ID: 7202]
“Carts used to transport partially stoppered vials should sanitized and monitored for viable contamination.”
11. The manufacturer should ensure, either by a written commitment or by a contract that he is notified
by the detergent supplier of any critical changes in the formulation of the detergent.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN
QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION,
CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation
4.9. Detergents
4.9.2.
[VIP ID: 69350]
“The composition of detergents should be known to the manufacturer. … The manufacturer should ensure, either by
a written commitment or by a contracts that he is notified by the detergent supplier of any critical changes in the
formulation of the detergent.”
1. Cleaning Validation is documented evidence that an approved cleaning procedure will provide
equipment which is suitable for processing of pharmaceutical products or active pharmaceutical
ingredients (APIs).
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
GLOSSARY - Definitions of terms relating to qualification and validation which are not given in the glossary of the
current PIC/S Guide to GMP, but which are used in this Annex, are given below.
Cleaning Validation
[VIP ID: 187124]
“Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is
suitable for processing medicinal products.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.1 Principle
7.1.3
[VIP ID: 188632]
“Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is
suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs).”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.1 Principle
7.1.4
[VIP ID: 188634]
“Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical
monitoring may be omitted or reduced to a minimum in the routine phase.”
2. The company's overall policy, intentions, and approach to validation, including the validation of
production processes, cleaning procedures, analytical methods, in-process control test procedures,
computerised systems, and persons responsible for design, review, approval and documentation of
each validation phase, should be documented.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.1 Validation Policy
12.10
[VIP ID: 24748]
“The company's overall policy, intentions, and approach to validation, including the validation of production
processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems,
and persons responsible for design, review, approval and documentation of each validation phase, should be
documented.”
3. The first step is to focus on the objective of the validation process, and we have seen that some
companies have failed to develop such objectives. It is not unusual to see manufacturers use
extensive sampling and testing programs following the cleaning process without ever really
evaluating the effectiveness of the steps used to clean the equipment. Several questions need to
be addressed when evaluating the cleaning process:
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
(para 1)
[VIP ID: 1329]
“The first step is to focus on the objective of the validation process, and we have seen that some companies have
failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing
programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean
the equipment. Several questions need to be addressed when evaluating the cleaning process…”
• For example, at what point does a piece of equipment or system become clean?
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.4
[VIP ID: 188646]
“Several questions should be addressed when evaluating the cleaning process. For example:
- At what point does a piece of equipment or system become clean?”
• How variable are manual cleaning processes from batch to batch and product to product?
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.4
[VIP ID: 188646]
“Several questions should be addressed when evaluating the cleaning process. For example:
- How variable are manual cleaning processes from batch to batch and product to product?”
• Are different cleaning processes required for different products in contact with a piece of
equipment?
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.4
[VIP ID: 188646]
“Several questions should be addressed when evaluating the cleaning process. For example:
- Are different cleaning processes required for different products in contact with a piece of equipment?”
• How many times need a cleaning process be applied to ensure adequate cleaning of each piece of
equipment?
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.4
[VIP ID: 188646]
“Several questions should be addressed when evaluating the cleaning process. For example:
- How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?”
4. The answers to these questions are obviously important to the inspection and evaluation of the
cleaning process since one must determine the overall effectiveness of the process. Answers to
these questions may also identify steps that can be eliminated for more effective measures and
result in resource savings for the company.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
(para 1)
[VIP ID: 1329]
“The answers to these questions are obviously important to the inspection and evaluation of the cleaning process
since one must determine the overall effectiveness of the process. Answers to these questions may also identify
steps that can be eliminated for more effective measures and result in resource savings for the company.”
1. be validated.
Extracted from FDA Warning Letter W/L 07/05 (January 2005)
USA
25/01/2005
[VIP ID: 134240]
“Failure to establish written procedures for the cleaning and maintenance of equipment used in the manufacture,
processing, packing, or holding of a drug product [21 CFR 211.67(b)]. For example, cleaning methods have not been
validated.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.1 Principle
7.1.2
[VIP ID: 188630]
“Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies
equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients (APIs). In any case,
manufacturing processes have to be designed and carried out in a way that contamination is reduced to an
acceptable level.”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.2
[VIP ID: 188642]
“Cleaning procedures for product changeover in the case of marketed products should be fully validated.”
PI 012-2
RECOMMENDATION ON
STERILITY TESTING (July 2004)
9. CLEANING, SANITISATION AND DISINFECTION
9.4
[VIP ID: 190290]
“Prior to implementation, all cleaning, sanitising and disinfecting procedures should be validated from a
microbiological perspective with respect to minimum disinfectant contact times and efficacy. Cleaning and
disinfecting agents should be purchased to agreed and documented specifications.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.70
[VIP ID: 24769]
“Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations
or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example,
in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed
by subsequent purification steps.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.70
[VIP ID: 155740]
“Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations
or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example,
in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed
by subsequent purification steps.”
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT
AND VALIDATION (January 1994)
III PRODUCT DEVELOPMENT
B. PRE-APPROVAL INSPECTIONS
To evaluate the proposed manufacturing process the following areas must be covered during the pre-approval
inspection:
7. Equipment
[VIP ID: 3103]
“…Manufacturers must validate their cleaning processes for the new drug/dosage form. FDA Warning Letter CBER-
01-023 (July 2001)”
PI 006-2
RECOMMENDATIONS ON
VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.10
[VIP ID: 188658]
“It is usually not considered acceptable to "test until clean". This concept involves cleaning, sampling and testing,
with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a
validated cleaning process, this practice of "test until clean" should not be required. The practice of "test until
clean" is not considered to replace the need to validate cleaning procedures.”
• Examine and evaluate the level of testing and the retest results since testing until clean is a concept
utilised by some manufacturers. They test, resample, and retest equipment or systems until an
"acceptable" residue level is attained. For the system or equipment with a validated cleaning
process, this practice of resampling should not be utilised and is acceptable only in rare cases.
Constant retesting and resampling can show that the cleaning process is not validated since these
retests actually document the presence of unacceptable residue and contaminants from an
ineffective cleaning process.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
c. Test Until Clean
[VIP ID: 1354]
“Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by
some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is
attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be
utilized and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process
is not validated since these retests actually document the presence of unacceptable residue and contaminants from
an ineffective cleaning process.”
6.3.1 General
1. not be executed until all of the associated analytical methods have been validated.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.10 Analytical Methods
7.10.1
[VIP ID: 188696]
“The analytical methods should be validated before the Cleaning Validation Study is carried out.”
3. include/reference the limit of detection and the limit of quantitation of the analytical methods to be
used.
Selected FDA 483 Observations (March 2001)
Laboratories
[VIP ID: 27260]
“Analytical methods used in cleaning validation should be shown to have suitable sample preparation, HPLC
operating conditions, and / or limits for quantification and detection.”
4. state the title of the individual(s) responsible for performing and approving the validation study.
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- Responsibilities for performing and approving the validation study,”
• The Cleaning Validation Protocol should be formally approved by the Plant Management to ensure
that aspects relating to the work defined in the protocol, for example personnel resources, are
known and accepted by the management. Quality Assurance should be involved in the approval of
protocols and reports.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.2
[VIP ID: 188664]
“The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects
relating to the work defined in the protocol, for example personnel resources, are known and accepted by the
management. Quality Assurance should be involved in the approval of protocols and reports.”
7. state the cleaning procedures to be used for each product, each manufacturing system or each
piece of equipment, including the rationale for use.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment,”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.72
[VIP ID: 24771]
“The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable
cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also
indicate the type of samples to be obtained and how they are collected and labelled.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.72
[VIP ID: 155760]
“The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.”
• Typically three consecutive applications of the cleaning procedure should be performed and shown
to be successful in order to prove that the method is validated.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION
40
[VIP ID: 187110]
“Typically three consecutive applications of the cleaning procedure should be performed and shown to be
successful in order to prove that the method is validated.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.6
[VIP ID: 188650]
“At least three consecutive applications of the cleaning procedure should be performed and shown to be successful
in order to prove that the method is validated.”
12. reflect actual worst case production conditions. (e.g. validation after the maximum number of
consecutive same product runs and/or the longest production campaigns)
Selected FDA 483 Observations (August 2007)
Product Manufacture
[VIP ID: 193904]
“Validation runs should be performed using worst case scenarios (i.e., most difficult to clean drug residues,
maximum holding time prior to or after equipment cleaning, etc.) to justify the currently-in-use equipment cleaning
procedures.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.71
[VIP ID: 24770]
“Validation of cleaning procedures should reflect actual equipment usage patterns.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.71
[VIP ID: 155750]
“Validation of cleaning procedures should reflect actual equipment usage patterns.”
14. include sampling procedures, including the rationale for why a certain sampling method is used.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- Sampling procedures, including the rationale for why a certain sampling method is used,”
• include the taking of bioburden samples from sample sites before cleaning.
Selected FDA 483 Observations (February 2006)
Sterile Product Manufacture
[VIP ID: 193140]
“Cleaning validation of equipment should include demonstration of worst case conditions such as the taking of
bioburden samples from sample sites before cleaning.”
16. include a description of the swab method to include how the samples are collected and the amount
of samples collected.
Selected FDA 483 Observations (July 2007)
Sterile Product Manufacture
[VIP ID: 193844]
“Validation data should be provided to support the surface monitoring procedure using the swab technique, and
recovery data should be available relating to the qualification of laboratory personnel in the execution of this
technique.”
18. data to support sampling procedures with swab techniques for microbiological surface monitoring of
equipment.
Selected FDA 483 Observations (March 2006)
Laboratories
[VIP ID: 193212]
“There should be validation data to support sampling procedures with swab techniques for microbiological surface
monitoring of equipment used in the manufacture of ointments, suspensions and solid dosage products, and
recovery data should be available relating to the qualification of personnel in the execution of these techniques.”
19. recovery data relating to the qualification of personnel in the execution of swab techniques for
microbiological surface monitoring.
Selected FDA 483 Observations (July 2007)
Sterile Product Manufacture
[VIP ID: 193844]
“Validation data should be provided to support the surface monitoring procedure using the swab technique, and
recovery data should be available relating to the qualification of laboratory personnel in the execution of this
technique.”
20. identify and provide a scientific rationale for the amount of rinse samples to be collected.
Selected FDA 483 Observations (June 2003)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 52760]
“Cleaning validation should include:
(b) a scientific rationale for the sampling sizes to determine residuals.”
21. include the rotation of sampling areas within the different equipment parts (specifically in the case of
cleaning validation for the evaluation of microbial load reduction in manufacturing or filling
equipment).
Selected FDA 483 Observations (February 2006)
Product Manufacture
[VIP ID: 193126]
“In the case of cleaning validation for the evaluation of microbial load reduction in manufacturing or filling
equipment, the evaluation should include the rotation of sampling areas within the different equipment parts.”
23. include specific instructions to ensure that repeat samples are not taken from identical locations.
Selected FDA 483 Observations (October 1998)
Product Manufacture
[VIP ID: 6843]
“Cleaning swab sample procedures should ensure that repeat samples are not taken from identical locations.”
• include specific instructions to ensure that micro and chemical samples are not collected from the
same areas.
Selected FDA 483 Observations (February 1997)
Product Manufacture
[VIP ID: 2470]
“Cleaning validation protocols / SOPs should include specific instructions to ensure that microbiological and
chemical samples are not collected from the same areas.”
25. require swabbing the hardest to clean areas (gaskets, sample ports, glass windows, etc.).
Selected FDA 483 Observations (August 2007)
Product Manufacture
[VIP ID: 193906]
“The efficacy of currently-in-use equipment cleaning procedures should not be based only on the routine analysis of
rinse samples, but should also evaluate the most difficult to clean surfaces and/or areas of the equipment with the
use of swabs.”
27. include the demonstration of endotoxins reduction for rubber closure components (stoppers, pistons
and caps) used in sterile product manufacture.
Selected FDA 483 Observations (March 2000)
Sterile Product Manufacture
[VIP ID: 15040]
“Cleaning validation of washing processes for rubber closure components (stoppers, pistons and caps) should
include the reduction of endotoxins.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.75
[VIP ID: 24774]
“Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those
processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes
where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.75
[VIP ID: 155790]
“Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those
processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes
where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).”
29. include microbial load reduction for oral solid dosage manufacturing equipment.
Selected FDA 483 Observations (February 2006)
Product Manufacture
[VIP ID: 193120]
“Cleaning procedures for oral solid dosage manufacturing equipment should be validated for microbial load
reduction.”
30. include clear acceptance criteria with a supporting rationale for setting the specific limits.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION
36
[VIP ID: 187102]
“Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The
rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should
be logically based on the materials involved. The limits should be achievable and verifiable.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.25
[VIP ID: 24570]
“Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and
justified.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.25
[VIP ID: 154020]
“Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and
justified.”
• include the correlation between detergent and product residue acceptance criteria and maximum
daily therapeutic dose limits where applicable.
Selected FDA 483 Observations (April 2003)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 52380]
“Cleaning validation should include the correlation between detergent and product residue acceptance criteria and
maximum daily therapeutic dose limits.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- Data on recovery studies where appropriate,”
32. address the control of residues of the solvents used in the manufacturing process.
ICH HARMONISED TRIPARTITE GUIDELINE IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2) (October 2006)
3. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES
3.3 Solvents
[VIP ID: 184444]
“The control of residues of the solvents used in the manufacturing process for the new drug substance should be
discussed and presented according to the ICH Q3C Guideline for Residual Solvents.”
35. include data on the evaluation for the PAD (Pharmaceutically Active Dose) value that was
determined.
Selected FDA 483 Observations (May 2004)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 122470]
“API Cleaning Validation protocols should include:
f. data on the evaluation for the PAD (Pharmaceutically Active Dose) value that was determined.”
38. state whether acceptance criteria are to be applied to individual samples or averages.
Selected FDA 483 Observations (November 2000)
Product Manufacture
[VIP ID: 26190]
“Cleaning validation should include:
(3) a statement as to whether acceptance criteria are to be applied to individual samples or averages”
39. include a demonstration that the testing of unclean equipment yields unacceptable results.
Selected FDA 483 Observations (January 1999)
Product Manufacture
[VIP ID: 7096]
“Cleaning validation should include recovery tests and a demonstration that the testing of unclean equipment yields
unacceptable results.”
40. demonstrate the adequate removal of media used as part of media fills.
Extracted from FDA Warning Letter FLA-03-19 (January 2003)
USA
06/01/2003
[VIP ID: 58520]
“4(c). Your firm did not validate and approve according to established procedures a process whose results cannot
be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(b). Specifically:
(c) Your firm has not determined whether the cleaning process for the BFS machine adequately removes media
used as part of media fills.”
41. consider vapours, such as oil vapours, when compressed air is used as part of the cleaning
process.
GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994)
XI. PACKAGING
(para 2)
[VIP ID: 3239]
“Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to filling. Fibers and
even insects have been identified as debris in containers, and particularly plastic containers used for these
products. Many manufacturers receive containers shrink-wrapped in plastic to minimize contamination from
fiberboard cartons. Many manufacturers utilize compressed air to clean containers. Vapors, such as oil vapors, from
the compressed air have occasionally been found to present problems. Review the firm's systems for the cleaning
of containers.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
REVALIDATION
45
[VIP ID: 187120]
“Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that
they remain valid. Where no significant changes have been made to the validated status, a review with evidence that
facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- When Re-validation will be required.”
COMPLIANCE PROGRAM GUIDANCE MANUAL FOR FDA STAFF: DRUG MANUFACTURING INSPECTIONS
PROGRAM 7356.002 (February 2002)
PART III - INSPECTIONAL
INVESTIGATIONAL OPERATIONS
C. System Inspection Coverage
PRODUCTION SYSTEM
[VIP ID: 61590]
“For each of the following, the firm should have written and approved procedures and documentation resulting
therefrom. The firm's adherence to written procedures should be verified through observation whenever possible.
These areas are not limited to finished products, but may also incorporate components and in-process materials.
These areas may indicate deficiencies not only in this system but also in other systems that would warrant
expansion of coverage. When this system is selected for coverage in addition to the Quality System, all areas listed
below should be covered; however, the depth of coverage may vary depending upon inspectional findings.
- change control; the need for revalidation evaluated”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
6. NON-STERILE PROCESS VALIDATION
6.6 Re-validation
6.6.5
[VIP ID: 188618]
“The need for periodic Re-validation of non-sterile processes is considered to be a lower priority than for sterile
processes. In the case of standard processes on conventional equipment a data review similar to what would be
required for Retrospective Validation may provide an adequate assurance that the process continues under control.
In addition the following points should also be considered:
(e) Cleaning and hygiene programme still appropriate,”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.8
[VIP ID: 188654]
“Control of change to validated cleaning procedures is required. Re-validation should be considered under the
following circumstances:
(a) Re-validation in cases of changes to equipment, products or processes,
(b) Periodic Re-validation at defined intervals.”
• Re-validation should include more than one run and one set of results.
Selected FDA 483 Observations (September 2004)
Sterile Product Manufacture
[VIP ID: 124000]
“Revalidation of equipment cleaning and sanitization validations should include more than one run and one set of
results.”
• Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP)
systems.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.9
[VIP ID: 188656]
“Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.”
43. include the rationale for the cleaning of additional products introduced when validation is complete.
Selected FDA 483 Observations (July 2000)
Product Manufacture
[VIP ID: 19280]
“Cleaning validation protocols should address:
(2) the rationale for the cleaning of additional products introduced when validation is completed.”
44. address all the products (to include pharmaceutical compounds and intermediates) processed
using a particular item of equipment.
Extracted from FDA warning letter 07-NWJ-06 (February 2007)
USA
01-Feb-07
7. a)
[VIP ID: 194842]
“Your firm's cleaning validation studies were found to be inadequate and, as a result, there was no assurance that
equipment is adequately cleaned between the manufacture of different drug products. [21 CFR 211.67(b)] For
example:
a) Cleaning validation was performed for the process trains without evaluating for sample recovery for numerous
products, including: Amidal Nasal Decongestant; Amigesic Caplets, 750mg; Carisoprodol and Aspirin Tablets, USP,
200mg/325mg; Carisoprodol Tablets, USP, 350mg; Chlorzoxazone Tablets, USP, 250mg and 500mg; Digoxin Tablets,
USP, 0.25mg.”
• Cleaning procedures for products and processes which are very similar, do not need to be
individually validated. It is considered acceptable to select a representative range of similar
products and processes concerned and to justify a validation programme which addresses the
critical issues relating to the selected products and processes. A single validation study under
consideration of the "worst case" can then be carried out which takes account of the relevant
criteria. This practice is termed "Bracketing".
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION
39
[VIP ID: 187108]
“For cleaning procedures for products and processes which are similar, it is considered acceptable to select a
representative range of similar products and processes. A single validation study utilising a "worst case" approach
can be carried out which takes account of the critical issues.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.5
[VIP ID: 188648]
“Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It
is considered acceptable to select a representative range of similar products and processes concerned and to
justify a validation programme which addresses the critical issues relating to the selected products and processes.
A single validation study under consideration of the "worst case" can then be carried out which takes account of the
relevant criteria. This practice is termed "Bracketing".”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.11 Establishment of Limits
7.11.2
[VIP ID: 188704]
“The approach for setting limits can be:
- product specific Cleaning Validation for all products,
- grouping into product families and choosing a "worst case" product,
- grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).”
• Products which simulate the physicochemical properties of the substances to be removed may
exceptionally be used instead of the substances themselves, where such substances are either
toxic or hazardous.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION
42
[VIP ID: 187114]
“Products which simulate the physicochemical properties of the substances to be removed may exceptionally be
used instead of the substances themselves, where such substances are either toxic or hazardous.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.3 General
7.3.11
[VIP ID: 188660]
“Products which simulate the physicochemical properties of the substance to be removed may be used instead of
the substances themselves, where such substances are either toxic or hazardous.”
45. evaluate the cleaning of all equipment and ancillary equipment that can be used for each product
category.
Selected FDA 483 Observations (June 2002)
Product Manufacture
[VIP ID: 47110]
“Cleaning validation should evaluate all of the cleaning procedures used for each product category.”
47. include other products, processes and equipment for which the planned validation is valid according
to a "bracketing" concept.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- Other products, processes, and equipment for which the planned validation is valid according to a "bracketing"
concept,”
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
(m) other products, processes and equipment for which the planned validation is valid according to a "bracketing"
concept,”
48. evaluate all of the cleaning procedures used for each product category.
Selected FDA 483 Observations (June 2002)
Product Manufacture
[VIP ID: 47120]
“Cleaning validation should evaluate the cleaning of all equipment that can be used for each product category.”
49. include the rationale / justification for the selection of products to be tested for 'worst case' scenario.
Extracted from FDA Warning Letter [NO REFERENCE] (August 2005)
Germany
30/08/2005
[VIP ID: 171820]
“3. Failure to adequately validate a process that cannot be fully verified by subsequent inspection and test, as
required by 21 CFR 820.75(a). For example the process validation documentation for the ultrasonic cleaning process
utilizing [redacted] lacks information to document that implants were cleaned according to the validation test plan
using worst case conditions.”
50. consider the most clinically significant (to include toxicity/potency) products.
Selected FDA 483 Observations (May 2004)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 122470]
“API Cleaning Validation protocols should include:
c. toxicological evaluation.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.71
[VIP ID: 24770]
“Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates
are manufactured in the same equipment and the equipment is cleaned by the same process, a representative
intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and
difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.71
[VIP ID: 155750]
“Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates
are manufactured in the same equipment and the equipment is cleaned by the same process, a representative
intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and
difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.71
[VIP ID: 155750]
“Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates
are manufactured in the same equipment and the equipment is cleaned by the same process, a representative
intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and
difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.”
• Choosing the most insoluble product with the highest blend may not always be the worst case for
cleaning validation. Consideration should also be given to excipients. A hard to clean excipient may
bond with a relatively soluble active ingredient to adhere to equipment walls.
Selected FDA 483 Observations (September 1999)
Product Manufacture
[VIP ID: 8310]
“Cleaning validation (matrix) studies should address and evaluate:
(1) removal of potential product degradents, drug/cleaning agent reaction products and excipients
(2) ability of analytical methods to detect potential product degradents, drug/cleaning agent reaction products and
excipients”
53. consider chemical variations (active decomposition materials) which may be difficult to remove.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN
QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION,
CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation
4.11. Establishment of Limits
4.11.5.
[VIP ID: 69430]
“In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical
variations (active decomposition materials) may be more difficult to remove.”
54. all primary packing operations of prescription and over-the-counter pharmaceutical products packed
in multi-use rooms.
Extracted from FDA Warning Letter W/L 77-00 (September 2000)
USA
22/09/2000
[VIP ID: 20230]
“1. Failure to establish and follow procedures for cleaning and maintenance of equipment [$211.67(b)]. For example,
cleaning validation has not been performed for any of your packaging lines. In addition, Standard Operating
Procedures (SOPS) regarding cleaning were not followed and resulted in `foreign` tablets present in product.”
60. include the entire time period during which cleaning agents are rotated.
Selected FDA 483 Observations (October 1998)
Sterile Product Manufacture
[VIP ID: 6855]
“Cleaning validation should include the entire time period during which cleaning agents are rotated.”
62. include the maximum length of time between the end of processing and each cleaning step.
Selected FDA 483 Observations (August 2007)
Product Manufacture
[VIP ID: 193904]
“Validation runs should be performed using worst case scenarios (i.e., most difficult to clean drug residues,
maximum holding time prior to or after equipment cleaning, etc.) to justify the currently-in-use equipment cleaning
procedures.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- The interval between the end of production and the beginning of the cleaning procedures,”
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
(d) the interval between the end of the production and the beginning of the cleaning procedures,”
63. include the maximum length of time between cleaning and the use of manufacturing equipment.
Selected FDA 483 Observations (December 2006)
Product Manufacture
[VIP ID: 194324]
“Cleaning validation, for equipment, which is not dedicated to one product, should include the evaluation of
microbiological control, a recovery study performed to demonstrate the sensitivity and specificity (detection limit) of
analytical equipment to demonstrate that residual product is removed after cleaning, documentation of the sampling
method or location used in the cleaning validation and the establishment of time limitation of cleaning prior to next
use.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.7 Microbiological Aspects
7.7.2
[VIP ID: 188684]
“The period and when appropriate, conditions of storage of equipment before cleaning and the time between
cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide
confidence that routine cleaning and storage of equipment does not allow microbial proliferation.”
64. include the maximum length of time between cleaning and drying of equipment where appropriate.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006)
ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS
SANITATION
50
[VIP ID: 186098]
“The interval between the washing and drying and the sterilisation of components, containers and equipment as
well as between their sterilisation and use should be minimised and subject to a time-limit appropriate to the storage
conditions.”
65. include a demonstration of the expiration dating of opened disinfectant concentrates used in the
cleaning of critical manufacturing areas.
Selected FDA 483 Observations (February 2006)
Sterile Product Manufacture
[VIP ID: 193138]
“Cleaning validation should include demonstration of the expiration dating of opened disinfectant concentrates
used in the cleaning of critical manufacturing areas.”
66. include when appropriate, the conditions of storage of equipment before and after cleaning.
NOTE: This is to provide confidence that routine cleaning and storage of equipment does not
allow microbial proliferation.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN
QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION,
CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation
4.7. Microbiological Aspects
4.7.2.
[VIP ID: 69270]
“The period and when appropriate, the conditions of storage of equipment before and after cleaning and the time
between cleaning and equipment re-use, should form part of the validation of cleaning procedures. This is to
provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.”
67. assess such parameters as flow rate, agitator speed and mixing time.
Selected FDA 483 Observations (May 1997)
Sterile Product Manufacture
[VIP ID: 2534]
“Cleaning Validation should include:
(4) assessment of the flow rate of the water, agitator speed and mixing time”
68. include minimum flow rates, flush times and flush quantities specified in cleaning procedures..
Selected FDA 483 Observations (March 2005)
Sterile Product Manufacture
[VIP ID: 138870]
“Equipment cleaning validation studies should demonstrate that cleaning is effective at the minimum flow rates,
flush times and flush quantities specified in cleaning procedures.”
69. include minimum rinse times and / or minimum cleaning solution contact times.
Selected FDA 483 Observations (March 2000)
Sterile Product Manufacture
[VIP ID: 15280]
“Cleaning validation should include the evaluation of:
(1) minimum rinse times
(3) and / or minimum cleaning solution contact times”
70. demonstrate that the rinse contacts all of the product contact surfaces.
Selected FDA 483 Observations (December 1998)
Sterile Product Manufacture
[VIP ID: 7067]
“Cleaning validation should include:
2) demonstration that the rinse contacts all product contact surfaces”
71. confirm that residual water is removed from the equipment following cleaning.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.7 Microbiological Aspects
7.7.3
[VIP ID: 188686]
“In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to
remain in equipment subsequent to cleaning operations.”
72. include the production equipment used during media fill runs.
Selected FDA 483 Observations (December 1999)
Sterile Product Manufacture
[VIP ID: 14260]
“Cleaning validation should include the production equipment used during media fill runs.”
• Cleaning/depyrogenation validation of tubing used in sterile filtration should include data for the
level of endotoxins on the tubing prior to depyrogenation.
Selected FDA 483 Observations (March 2000)
Sterile Product Manufacture
[VIP ID: 15270]
“Cleaning / depyrogenation validation of tubing used in sterile filtration should include data for the level of
endotoxins on the tubing prior to depyrogenation.”
75. include miscellaneous items used during aseptic operations, such as pens, calculators, cable
cutters, walkie-talkies and printer paper.
Selected FDA 483 Observations (March 2005)
Sterile Product Manufacture
[VIP ID: 138860]
“Cleaning validation should be performed to demonstrate sanitisation of miscellaneous items used during aseptic
operations, such as pens, calculators, cable cutters and walkie-talkies, and there should be documentation that
these items are routinely sanitised.”
• Validation data should be generated to show that the procedure used to sanitise / disinfect
materials taken into the sterile fill rooms (i.e. writing pens, mops, and mop buckets) are effective.
Selected FDA 483 Observations (November 2002)
Sterile Product Manufacture
[VIP ID: 51590]
“Validation data should be generated to show that the procedure used to sanitize / disinfect materials taken into the
sterile fill rooms (i.e. writing pens, mops, and mop buckets) are effective.”
6.3.2 SOPs
1. require swab samples to be collected from the removable tray/bowl, and top portion, i.e. the filter
plenum.
Selected FDA 483 Observations (November 2006)
Product Manufacture
[VIP ID: 194188]
“During cleaning validation studies for a fluid bed dryer, swab samples should not just be collected from the
removable tray/bowl, but also from the top portion, i.e. the filter plenum, …”
2. include an evaluation of the cleaning process for non dedicated filter bags.
Selected FDA 483 Observations (November 2006)
Product Manufacture
[VIP ID: 194188]
“During cleaning validation studies for a fluid bed dryer, swab samples should not just be collected from the
removable tray/bowl, but also from the top portion, i.e. the filter plenum, and there should be an evaluation made of
the cleaning process for non dedicated filter bags.”
3. require cleaning validation samples to be collected on the same day the equipment is used, if the
fluid bed dryer is routinely cleaned after use.
Selected FDA 483 Observations (November 2006)
Product Manufacture
[VIP ID: 194188]
“… Cleaning validation samples should only be collected from the fluid bed dryer on the same day the equipment is
used, if the fluid bed dryer is routinely cleaned after use.”
1. Tablet Press cleaning validation should include the identification of the punches and dies used.
Selected FDA 483 Observations (March 2001)
Product Manufacture
[VIP ID: 27360]
“Tablet Press cleaning validation should include the identification of the punches and dies used.”
1. complete solubility studies between the cleaning agent(s) and all active and inactive ingredients.
Selected FDA 483 Observations (December 2000)
Sterile Product Manufacture
[VIP ID: 26300]
“Cleaning validation of sterile injectable products should include:
(a) Complete solubility studies between the cleaning agent(s) and all active and inactive ingredients.”
6.3.6 Centrifuge
6.3.7 Lyophilizer
1. the requirement to sample the chamber both before and after cleaning to confirm the absence of oil
vapour which may have migrated back to the chamber from the vacuum pump.
GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993)
Lyophilization Cycle and Controls
(para 11)
[VIP ID: 2779]
“In order to minimize oil vapor migration, some lyophilizers are designed with a tortuous path between the vacuum
pump and chamber. For example, one fabricator installed an oil trap in the line between the vacuum pump and
chamber in a lyophilizer with an internal condenser. Leakage can also be identified by sampling surfaces in the
chamber after lyophilization for contaminants. One could conclude that if contamination is found on a chamber
surface after lyophilization, then dosage units in the chamber could also be contaminated. It is a good practice as
part of the validation of cleaning of the lyophilization chamber to sample the surfaces both before and after
cleaning.”
4. testing the ram hydraulic fluid (where used) for its bacteriostatic effectiveness.
GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993)
Lyophilizer Sterilization/Design
(para 9)
[VIP ID: 2793]
“In some of the larger units, the shelves are collapsed after sterilization to facilitate loading. Obviously, the portions
of the ram entering the chamber to collapse the shelves enters from a non-sterile area. Attempts to minimize
contamination have included wiping the ram with a sanitizing agent prior to loading. Control aspects have included
testing the … fluid for its bacteriostatic effectiveness. ...”
5. the maximum challenge of glass fragments from broken/cracked vials as observed through routine
production.
Selected FDA 483 Observations (January 2005)
Sterile Product Manufacture
[VIP ID: 138020]
“There should be cleaning validation studies or specific procedural requirements to address the elimination of glass
particles from broken vials, or residuals from product spilled as a result of breakages on machines.”
6. the screens or wire electrodes that have product contact during lyophilization.
Extracted from FDA Warning Letter WL-24-02 (January 2002)
USA
14/01/2002
1
[VIP ID: 48080]
“1. … There is no cleaning validation for screens or wire electrodes that have product contact during lyophilization.
Our investigators also observed foreign substances on production screens and trays.”
Non-dedicated (multi-use) primary packaging equipment cleaning validation protocols should include:
1. microbial evaluations for use in risk assessment.
2. the identification of worst case toxicity/potency and cleanability/solubility products.
3. assessment of all equipment train configurations.
4. the documentation of the cleaning of equipment at the time of occurrence in equipment cleaning
and use logs.”
Selected FDA 483 Observations (May 2004)
Packaging & Labelling
[VIP ID: 122290]
“Cleaning validation of non dedicated (multi-use) primary packaging equipment should include:
a. microbial evaluations for use in risk assessment.
b. the identification of worst case toxicity/potency and cleanability/solubility products.
c. assessment of all equipment train configurations.
d. the documentation of the cleaning of equipment at the time of occurrence in equipment cleaning and use logs.”
3. include spiking the stoppers with known amounts of endotoxin to determine if the washer is
effective in de-pyrogenating stoppers.
Selected FDA 483 Observations (December 2001)
Sterile Product Manufacture
[VIP ID: 45990]
“Stopper washer validation should include:
(a) Spiking the stoppers with known amounts of endotoxin to determine if the washer is effective in de-pyrogenating
stoppers.”
1. include the determination of the lot to lot variability of the cleaning agent.
Selected FDA 483 Observations (April 2000)
Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(1) determination of the lot to lot variability of the cleaning agent”
3. include the periodic challenging of sanitisers with new resistant isolates such as Bacillus
lichenformis and Bacillus thurigenesis.
Selected FDA 483 Observations (April 2000)
Sterile Product Manufacture
[VIP ID: 15660]
“Environmental monitoring should include:
(2) periodic challenging of sanitizers with new resistant isolates such as Bacillus lichenformis and Bacillus
thurigenesis”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.25
[VIP ID: 154020]
“Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and
justified.”
6. demonstrate that the cleaning agent dilution procedure produces the optimum level for cleaning and
disinfection.
Selected FDA 483 Observations (October 1998)
Sterile Product Manufacture
[VIP ID: 6856]
“The cleaning agent dilution procedure should be demonstrated to produce the optimum level for cleaning and
disinfection.”
7. demonstrate the effectiveness of the cleaning agents to establish satisfactory levels of kill within an
acceptable exposure time against isolated environmental contaminants.
Selected FDA 483 Observations (December 2002)
Product Manufacture
[VIP ID: 51780]
“The suitability of equipment cleaning agents should be validated to confirm their effectiveness.”
8. demonstrate the compatibility between the cleaning agent(s) and the drug product(s).
Selected FDA 483 Observations (October 1999)
Product Manufacture
[VIP ID: 8590]
“The compatibility between cleaning agents and drug products should be determined.”
1. There are two methods of sampling that are considered to be acceptable, direct surface sampling
(swab method) and indirect sampling (use of rinse solutions).
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.8 Sampling
7.8.2
[VIP ID: 188690]
“There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method)
and indirect sampling (use of rinse solutions).”
• A combination of the two methods is generally the most desirable, particularly in circumstances
where accessibility of equipment parts can mitigate against direct surface sampling.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.8 Sampling
7.8.2
[VIP ID: 188690]
“…A combination of the two methods is generally the most desirable, particularly in circumstances where
accessibility of equipment parts can mitigate against direct surface sampling.
A. Direct Surface Sampling
(i) The suitability of the material to be used for sampling and of the sampling medium should be determined. The
ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure
that the sampling medium and solvent are satisfactory and can be readily used.
B. Rinse Samples
(i) Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be
routinely disassembled can be evaluated. However, consideration should be given to the solubility of the
contaminant.
(ii) A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse
samples are used to validate the cleaning process.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.73
[VIP ID: 24772]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to
detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively
measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be
impractical when product contact surfaces are not easily accessible due to equipment design and / or process
limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials,
and small intricate equipment such as micronizers and microfluidizers).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.73
[VIP ID: 155770]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to
detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively
measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be
impractical when product contact surfaces are not easily accessible due to equipment design and/or process
limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials,
and small intricate equipment such as micronizers and microfluidizers).”
2. An advantage of direct sampling is that "dried out" or insoluble residues can be sampled by physical
removal.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
4. Sampling
a. Direct Surface Sampling -
(para 2)
[VIP ID: 1343]
“Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be
evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues
that are "dried out" or are insoluble can be sampled by physical removal.”
3. Cleaning validation should include swab testing, and not rely solely on rinse water analysis.
Selected FDA 483 Observations (December 2000)
Sterile Product Manufacture
[VIP ID: 26500]
“Cleaning validation should include swab testing, and not rely solely on rinse water analysis.”
4. Two advantages of using rinse samples are that a larger surface area may be sampled, and
inaccessible systems or ones that cannot be routinely disassembled can be sampled and
evaluated.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.73
[VIP ID: 24772]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to
detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively
measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be
impractical when product contact surfaces are not easily accessible due to equipment design and / or process
limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials,
and small intricate equipment such as micronizers and microfluidizers).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.73
[VIP ID: 155770]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to
detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively
measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be
impractical when product contact surfaces are not easily accessible due to equipment design and/or process
limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials,
and small intricate equipment such as micronizers and microfluidizers).”
5. A disadvantage of indirect (rinse) samples is that the residue or contaminant may not be soluble or
may be physically occluded in the equipment.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN
QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION,
CLEANING VALIDATION - SUPERSEDED!! (October 1999)
4. Cleaning Validation
4.8. Sampling
4.8.2.
(para 1) b.
[VIP ID: 69320]
“Rinse Samples
Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be
routinely disassembled can be evaluated. However, consideration should be given to the solubility of the
contaminant and the appropriate volume of the samples.”
• An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly
with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the
pot.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
4. Sampling
b. Rinse Samples -
(para 2)
[VIP ID: 1345]
“… An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried
out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.”
1. Rinse water samples should be analysed separately for the presence of product and cleaning agent
residues.
Selected FDA 483 Observations (July 2000)
Product Manufacture
[VIP ID: 19290]
“Cleaning rinse samples should be analyzed separately for active and detergent residues, not just for total
impurities.”
• Check to see that a direct measurement of the residue or contaminant has been made for the rinse
water when it is used to validate the cleaning process. For example, it is not acceptable to simply
test rinse water for water quality (does it meet the compendia tests) rather than test it for potential
contaminates.
Selected FDA 483 Observations (November 2003)
Product Manufacture
[VIP ID: 72300]
“Cleaning Validation Protocols should include:
c. Rinse water testing for the detection of active ingredient residues. (Only conducting USP water tests on rinse
samples is not enough).”
2. Rinse water samples should account for the fact that the residue may not be homogeneously
distributed through the rinse (possibly the first portion of the rinse contains a different amount than
the other portions).
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.11 Establishment of Limits
7.11.4
[VIP ID: 188708]
“One cannot ensure that the contaminate will be uniformly distributed throughout the system.”
• It is an invalid conclusion to make the assumption that a residual contaminant would be worn off the
equipment surface uniformly or that the contamination might only occur at the beginning of the
batch.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.11 Establishment of Limits
7.11.4
[VIP ID: 188708]
“… It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the
equipment surface uniformly or that the contamination might only occur at the beginning of the batch.”
3. The results from the analysis of rinse waters are meaningless unless the following information is
known:
• the volume of the rinse.
• the rinse contact surface area.
• the time of contact with surface area.
• the temperature of the rinse.
The following points should be considered for companies verifying cleaning using a placebo batch:
1. One cannot assure that the contaminant will be uniformly distributed throughout the system.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
a. Placebo Product -
(para 2)
[VIP ID: 1351]
“One cannot assure that the contaminate will be uniformly distributed throughout the system.”
• For example, if the discharge valve or chute of a blender are contaminated, the contaminant would
most likely be concentrated in the initial discharge portion of the placebo batch.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
a. Placebo Product -
(para 2)
[VIP ID: 1351]
“…For example, if the discharge valve or chute of a blender are contaminated, the contaminant would probably not
be uniformly dispersed in the placebo; it would most likely be concentrated in the initial discharge portion of the
batch.”
2. If the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the
placebo batch.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
a. Placebo Product -
(para 2)
[VIP ID: 1351]
“…Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the
placebo.”
3. The assumption that a residual contaminant would be worn off the equipment surface uniformly is
invalid.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
a. Placebo Product -
(para 3)
[VIP ID: 1352]
“Some firms have made the assumption that a residual contaminant would be worn off the equipment surface
uniformly; this is also an invalid conclusion. ...”
4. The analytical power may be greatly reduced by dilution of the contaminant in the placebo batch.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
a. Placebo Product -
(para 3)
[VIP ID: 1352]
“... Finally, the analytical power may be greatly reduced by dilution of the contaminate. ...”
5. Swab and/or rinse samples should be used in conjunction with the placebo method.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
a. Placebo Product -
(para 3)
[VIP ID: 1352]
“… Because of such problems, rinse and / or swab samples should be used in conjunction with the placebo
method.
[VIP NOTE: This sentence would appear to contradict an earlier stated preference of swabs over rinses. We believe
this should have read "…,swab and / or rinse samples…".]”
6.7 Swabs
• If a residue is found, it may not necessarily be at the maximum detectable level due to the random
sampling, such as taking a swab from a limited area on a piece of equipment.
GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994)
V. CLEANING VALIDATION
Equipment Residue Limits
(para 2)
[VIP ID: 119320]
“Because surface residues will not be uniform, it should be recognized that a detected residue level may not
represent the maximum amount that may be present. This is particularly true when surface sampling by swabs is
performed on equipment.”
2. The results from the analysis of swabs are meaningless unless the swab surface area is known.
Selected FDA 483 Observations (November 2000)
Product Manufacture
[VIP ID: 26190]
“Cleaning validation should include:
(5) swab areas”
3. The same swabbing procedure should be used for cleaning validation and swab recovery studies.
Selected FDA 483 Observations (November 2000)
Product Manufacture
[VIP ID: 26200]
“The swabbing procedure used during cleaning validation should be the same as that used for the swab recovery
study.”
1. For parenteral products, final rinse water should meet the specifications of WFI, USP.
GUIDANCE FOR INDUSTRY
STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING
- CURRENT GOOD MANUFACTURING PRACTICE (September 2004)
VI. Components and Container/Closures
B. Containers/Closures
1. Preparation
(para 2)
[VIP ID: 110760]
“Pre-sterilization preparation of glass containers usually involves a series of wash and rinse cycles. These cycles
serve an important role in removing foreign matter. We recommend use of rinse water of high purity so as not to
contaminate containers. For parenteral products, final rinse water should meet the specifications of WFI, USP.”
1. demonstrate that the methods used to collect cleaning samples are reliable, and that therefore the
results are representative and reproducible.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.10 Analytical Methods
7.10.3
[VIP ID: 188700]
“The analytical methods should be challenged in combination with the sampling methods used, to show that the
contaminants can be recovered from the equipment surface and to show the level of recovery as well as the
consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A
negative result may also be the result of poor sampling techniques.”
2. include the determination of the limit of detection and quantitation of the test method for products,
product degradents, cleaning agents, drug/cleaning agent reaction products and excipients.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be
validated. It should include the following:
- Analytical methods including the limit of detection and the limit of quantitation of those methods,”
• Determine the specificity and sensitivity of the analytical method used to detect residuals or
contaminants. If levels of contamination or residual are not detected, it does not mean that there is
no residual contaminant present after cleaning. It only means that levels of contaminant greater
than the sensitivity or detection limit of the analytical method are not present in the sample.
Selected FDA 483 Observations (August 2007)
Laboratories
[VIP ID: 193978]
“The specificity of test methods should be documented. For example, instructions for the identification and
quantification of peaks when using integrators should be provided, and integrated peaks in the swab samples taken
during cleaning validation runs eluting close to the retention time of the standard peak should be identified or
quantified during the validation exercise.”
4. include the evaluation of the method against more sensitive test methods where available (e.g.
HPLC), to ensure adequate specificity and sensitivity of impurity detection.
Selected FDA 483 Observations (April 1998)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 6372]
“Cleaning validation analytical methods should be evaluated against more sensitive test methods where available
(e.g. HPLC), to ensure adequate specificity and sensitivity of impurity detection.”
5. include recovery studies that require the application of an active to a coupon or template which
replicates the equipment surface.
Extracted from FDA warning letter 07-NWJ-06 (February 2007)
USA
01-Feb-07
7. b)
[VIP ID: 194844]
“Your firm's cleaning validation studies were found to be inadequate and, as a result, there was no assurance that
equipment is adequately cleaned between the manufacture of different drug products. [21 CFR 211.67(b)] For
example:
b) Recovery studies were performed for numerous drug products by applying a known amount of active
pharmaceutical ingredient directly to a swab, instead of applying the active to a coupon or template which would
replicate the equipment surface from which the active pharmaceutical ingredient should have been swabbed. The
products involved, included: Busipirone HCl Tablets, Hydrocodone Bitartrate and Homatropine Methylbromide
Tablets, Mirtazapine Tablets, Oxycodone and Acetaminophen Capsules USP.”
6. include a challenge to the sampling method (i.e. swabbing) to show that the recoveries can be
obtained at the specified limits.
Selected FDA 483 Observations (January 2003)
Product Manufacture
[VIP ID: 51890]
“Cleaning validation should include a challenge to the sampling method (i.e. swabbing) to show that the recoveries
can be obtained at the specified limits.”
• The firm should challenge the analytical method in combination with the sampling method(s) used
to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50%
recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample
results.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
3. Analytical Methods
[VIP ID: 1340]
“…The firm should challenge the analytical method in combination with the sampling method(s) used to show that
contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is
necessary before any conclusions can be made based on the sample results.”
• The worst case result should be used to calculate a swab recovery factor for cleaning validation, to
ensure that the actual contamination is not higher than calculated.
Selected FDA 483 Observations (October 1997)
Product Manufacture
[VIP ID: 2483]
“The worst case result should be used to calculate a swab recover factor for cleaning validation, to ensure that the
actual contamination is not higher than calculated.”
9. include the determination of the type of sampling materials used (the sampling medium and solvent
used for extraction from the medium) and its impact on the test data.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
4. Sampling
a. Direct Surface Sampling -
(para 1)
[VIP ID: 1342]
“Determine the type of sampling material used and its impact on the test data since the sampling material may
interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of
samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent
(used for extraction from the medium) are satisfactory and can be readily used.”
• For example, the adhesive used in swabs has been found to interfere with the analysis of samples.
Selected FDA 483 Observations (January 2002)
Product Manufacture
[VIP ID: 46280]
“Cleaning validation should include:
(b) Assurance that the type of swab used does not contribute interference to the analytical method.”
10. include raw data regarding standard and sample preparations, equipment used, reference
standards used etc.
Selected FDA 483 Observations (September 2001)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 40950]
“Cleaning validation studies should include raw data regarding standard and sample preparations, equipment used,
reference standards used etc.”
11. include testing to determine the types of residues obtained from the detergent(s) used.
Selected FDA 483 Observations (July 2000)
Product Manufacture
[VIP ID: 19300]
“Cleaning validation should include testing to determine the types of residues obtained from the detergent(s) used.”
12. include all surfaces the disinfectant is used on (such as glass, plastic and epoxy painted surfaces),
not just stainless steel.
Selected FDA 483 Observations (March 2003)
Product Manufacture
[VIP ID: 52180]
“The qualification of disinfecting agents used to sanitize surfaces in aseptic processing areas (APA) should address
all surfaces in the area not just stainless steel (such as glass, plastic and epoxy painted surfaces).”
13. include the determination of the solubility of product and excipient residues in the rinse solvent.
Selected FDA 483 Observations (August 2004)
Product Manufacture
[VIP ID: 123660]
“Cleaning procedures for Vacuum Blenders should be validated to include:
b. a solubility study to determine which products are hardest to clean”
14. include the following for production Spectrophotometers used to determine the contaminant
concentration in rinse samples:
• assurance that passing test results are within the limits of detection.
• justification for the use of sample blanks.
• assurance that reported sample test results are accurate.
• written procedures for testing rinse samples using blank standards.
• information or data on negative absorbance test results.”
Selected FDA 483 Observations (September 2003)
Laboratories
[VIP ID: 70180]
“Method validation for production Spectrophotometers used to determine the contaminant concentration in rinse
samples to assure effectiveness of manual cleaning processes between production runs should include:
- assurance that passing test results are within the limits of detection.
- justification for the use of sample blanks.
- assurance that reported sample test results are accurate.
- written procedures for testing rinse samples using blank standards.
- information or data on negative absorbance test results.”
15. challenge the ruggedness of the method by using different laboratories, analysts, days and
equipment.
Selected FDA 483 Observations (October 1999)
Laboratories
[VIP ID: 136760]
“The validation of analytical methods used to evaluate the effectiveness of equipment cleaning procedures should
challenge the ruggedness of the method by using different laboratories, analysts, days and equipment.”
The following points should be considered when establishing the cleaning validation acceptance limits:
1. Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?".
The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts
per million, down to parts per billion.
BIOTECHNOLOGY INSPECTION GUIDE (November 1991)
CLEANING PROCEDURES
C. Analytical Method/Cleaning Limits
(para 1)
[VIP ID: 1087]
“Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?" The sensitivity
of modern analytical apparatus has lowered some detection thresholds below parts per million (ppm), down to parts
per billion (ppb).”
2. FDA does not intend to set acceptance specifications or methods for determining whether a
cleaning process is validated. It is impractical for FDA to do so due to the wide variation in
equipment and products used throughout the bulk and finished dosage form industries.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
V. Establishment of Limits
(para 1)
[VIP ID: 1348]
“FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is
validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the
bulk and finished dosage form industries.”
3. The firm's rationale for the residue limits established should be logical based on the manufacturer's
knowledge of the materials involved and be practical, achievable, and verifiable.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.11 Establishment of Limits
7.11.1
[VIP ID: 188702]
“The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a
consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and
verifiable.”
• The manufacturer should be able to document, by means of data, that the residual level permitted
is scientifically sound.
Selected FDA 483 Observations (May 2004)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 122470]
“API Cleaning Validation protocols should include:
d. data for the maximum allowable limit not to exceed.”
4. Cleaning validation should include an explanation of how allowed residue limits will affect the next
synthesis stage or the next product type to be in contact with the equipment.
Selected FDA 483 Observations (January 2001)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 26570]
“Cleaning validation should include an explanation of how allowed residue limits will effect the next synthesis stage
or the next product type to be in contact with the equipment.”
5. Limits that have been mentioned by industry representatives in the literature or in presentations
include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the
normal therapeutic dose, and organoleptic levels such as no visible residue.
Selected FDA 483 Observations (August 1998)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 6766]
“BPC cleaning validation should include:
1) a rationale (considering toxicology etc) for the allowable carryover from the equipment”
6. Carry-over of product residues should meet defined criteria, for example the most stringent of the
following criteria:
(a) no more than 0.1% of the normal therapeutic dose of any product will appear in the maximum
daily dose of the following product,
(b) no more than 10 PPM of any product will appear in another product,
(c) no quantity of residue should be visible on the equipment after cleaning procedures are
performed. Spiking studies should determine the concentration at which most active
ingredients are visible,
(d) for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics,
the limit should be below the limit of detection by best available analytical methods. In practice
this may mean that dedicated plants are used for these products.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.11 Establishment of Limits
7.11.3
[VIP ID: 188706]
“Carry-over of product residues should meet defined criteria, for example the most stringent of the following three
criteria:
(a) No more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the
following product,
(b) No more than 10 ppm of any product will appear in another product,
(c) No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking
studies should determine the concentration at which most active ingredients are visible,
(d) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should
be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants
are used for these products.”
7. Consideration should be given to the cumulative effect on recirculated mother liquors as used in
API production.
Selected FDA 483 Observations (August 1998)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 6766]
“BPC cleaning validation should include:
3) the cumulative effect on recirculated mother liquors as used in production
8. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from
actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-
products which may never have been chemically identified. In establishing residual limits, it may not
be adequate to focus only on the principal reactant since other chemical variations may be more
difficult to remove. There are circumstances where TLC screening, in addition to chemical
analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some
steroids, the issue of by-products needs to be considered if equipment is not dedicated. The
objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.11 Establishment of Limits
7.11.5
[VIP ID: 188710]
“In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical
variations (active decomposition materials) may be more difficult to remove.”
9. Incidental carryover is another type of in-process mixing that occurs frequently. Examples include:
(a) Residue adhering to the wall of a micronizer used for milling the finished BPC;
(b) Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of
the crystals from a prior batch; and
(c) Incomplete discharge of fluids or crystals from a processing vessel upon transfer of the
material to the next step in the process.
These practices are usually acceptable since we do not normally require complete cleanup
between successive batches of the same drug during a production campaign. However, in the case
of non-dedicated production units, complete cleaning procedures designed to prevent
contamination that would alter the quality of the substance must be employed when changing from
one BPC to another. The effectiveness of these cleaning procedures may require the use of
analytical testing for the substances involved.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.24
[VIP ID: 24569]
“Non-dedicated equipment should be cleaned between production of different materials to prevent cross-
contamination.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.24
[VIP ID: 154010]
“Non-dedicated equipment should be cleaned between production of different materials to prevent cross-
contamination.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
5.23
[VIP ID: 154000]
“Where equipment is assigned to continuous production or campaign production of successive batches of the
same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over
of contaminants (e.g. degradants or objectionable levels of micro-organisms).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
8. PRODUCTION AND IN-PROCESS CONTROLS
8.5 Contamination Control
8.50
[VIP ID: 154920]
“Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate
control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in
a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon
transfer of the material to the next step in the process. Such carryover should not result in the carryover of
degradants or microbial contamination that may adversely alter the established API impurity profile.”
10. When the cleaning process is used only between batches of the same product (or different lots of
the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the
equipment. Such between batch cleaning processes do not require validation.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
(para 2)
[VIP ID: 1330]
“Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system
will have one process for cleaning, however this will depend on the products being produced and whether the
cleanup occurs between batches of the same product (as in a large campaign) or between batches of different
products. When the cleaning process is used only between batches of the same product (or different lots of the
same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such
between batch cleaning processes do not require validation.”
12. Sanitiser residue limits should be established for critical production areas (e.g. filling lines).
Selected FDA 483 Observations (May 1999)
Sterile Product Manufacture
[VIP ID: 7200]
“Sanitizer residue limits should be established for critical production areas (e.g. filling lines).”
13. If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise
when attempting to test for residues. A common problem associated with detergent use is its
composition. Many detergent suppliers will not provide specific composition, which makes it difficult
for the user to evaluate residues. As with product residues, it is important and it is expected that the
manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However,
unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very
low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process
and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily
removable. otherwise, a different detergent should be selected.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
VI. Other Issues
b. Detergent
[VIP ID: 1353]
“If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to
test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers
will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product
residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for
the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test
methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process
and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable.
otherwise, a different detergent should be selected.”
16. Water used in the cleaning of pharmaceutical equipment should be routinely monitored for chemical
and microbial contamination.
Selected FDA 483 Observations (April 2006)
Sterile Product Manufacture
[VIP ID: 193560]
“The quality of city water used in the initial rinsing of a fractionation CIP skid should be routinely assessed at point
of use.”
17. Endotoxin limits should be established for water used in the cleaning of equipment used in the
manufacture of APIs intended for parenteral use.
Selected FDA 483 Observations (July 2000)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 19220]
“Endotoxin limits should be established for water used in the cleaning of equipment used in the manufacture of
API's intended for parenteral use.”
18. API residue limits should be based on the minimum known pharmacological, toxicological, or
physiological activity of the API or its most deleterious component.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES
USED AS STARTING MATERIALS (October 2005)
12. VALIDATION
12.7 Cleaning Validation
12.74
[VIP ID: 24773]
“…Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can
be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or
its most deleterious component.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION
12.7 Cleaning Validation
12.74
[VIP ID: 155780]
“…Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can
be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or
its most deleterious component.”
19. Consideration should be given to the cumulative amount / variety of residues when defining the
allowable residue limits for rinses passing through multiple equipment items.
Selected FDA 483 Observations (June 2000)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 16440]
“Equipment cleaning validation should include:
(1) consideration of cumulative residue from more than one piece of equipment.
(2) calculate the total drug residue from multiple pieces of equipment in a production train”
20. Consideration should be given to the total surface area of the equipment when setting the
acceptance criterion and there should be written justification for the acceptance criterion.
Selected FDA 483 Observations (December 2006)
Product Manufacture
[VIP ID: 194286]
“… The surface area to be swabbed should be specified in the protocol or documented, the total surface area of the
equipment should be taken into account when setting the acceptance criterion and there should be written
justification for the acceptance criterion.”
• The conclusions of this report should state if the cleaning process has been validated successfully.
Limitations that apply to the use of the validated method should be defined (for example, the
analytical limit at which cleanliness can be determined).
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-
STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION
7.4 Documentation
7.4.3
[VIP ID: 188666]
“A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process
has been validated successfully. Limitations that apply to the use of the validated method should be defined (for
example, the analytical limit at which cleanliness can be determined).”
The following extracts have been taken from the FDA's "Human Drug CGMP Notes", which is a memo
issued to FDA personnel periodically to provide guidance on CGMP for human use pharmaceuticals.
These extracts supplement the information contained in the previous sections.
"Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of
contaminants in evaluating cleaning effectiveness?
Yes. Since the publication of the inspection guide on gleaning validation in 1993, a number of studies
have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning
validation. But in order for TOC to be functionally suitable, it should first be established that a substantial
amount of the contaminating material(s) is organic and contains carbon that can be oxidised under TOC
test conditions. This is not a trivial exercise because we know that some organic compounds can not be
reliably detected using TOC.
TOC may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In
either case TOC does not identify or distinguish among different compounds containing oxidizable
carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the
established limit. Thus, a firm should limit 'background' carbon (i.e. carbon from other sources other
than the contaminant being removed) as much as possible. The established limit -- or the amount of
residue detected for comparison to the spec -- should correct for the target material's composition of
carbon. As for any method, recovery studies are necessary. If TOC samples are being held for long
periods of time before analysis, a firm should verify the impact of sample hold time on accuracy and limit
of quantitation."
HUMAN DRUG CGMP NOTES, VOLUME 10, NUMBER 01 (First Quarter, 2002) (March 2002)
Brian J. Hasselbalch
QUESTIONS AND ANSWERS:
[Question 5]
[VIP ID: 71450]
"What is the level of detergent residue that would be acceptable to FDA? What is the basis for
arriving at this level, if any?
FDA has repeatedly stated that it is the firm's responsibility to establish acceptance limits and be
prepared to provide the basis for those limits to FDA. Thus, there is no fixed standard for levels of
detergent residue. Any residues must not adversely alter drug product safety, efficacy, quality, or
stability."
HUMAN DRUG CGMP NOTES, VOLUME 03, NUMBER 02 (June 1995)
Motise's Notebook
Policy Questions on Cleaning Validation:
1)
[VIP ID: 3930]
"If the ability of a procedure to clean a piece of equipment made of a particular material, such as
316 stainless steel, is shown to be acceptable and validated, can that "material" specific cleaning
procedure be used without "extensive" validation for other pieces of equipment and
compounds?
No. The design of the equipment is a major component of its cleanability. Therefore, firms should have
data that relate to a given piece of equipment."
HUMAN DRUG CGMP NOTES, VOLUME 03, NUMBER 02 (June 1995)
Motise's Notebook
Policy Questions on Cleaning Validation:
2)
[VIP ID: 3931]
"What cleaning and process validation do the CGMPs require for production of a bio-batch,
where only a single lot has been made?
The agency has not articulated its expectations regarding process validation or cleaning validation with
respect to bio-batches, per se. The closest relevant document is our Guideline on The Preparation of
Investigational New Drug Products. In that document we said:
At early clinical stages, where a single batch of drug product may be produced, and where significant
formulation and processing changes may make batch replication difficult or inexact, only limited process
validation may be possible. In such cases, limited validation, especially for such critical processes as
sterilisation, should be derived, to the extent possible, from product and process analogs. In addition,
data obtained from extensive in-process controls and intensive product testing may be used to
demonstrate that the instant run yielded a finished product meeting all of its specifications and quality
characteristics. It is expected that more comprehensive process validation will be conducted as
additional uniform batches are made under replicated conditions.
You may apply these principles to the bio-batch process and cleaning validation. We would expect
adequate cleaning to have been performed and documented and that in-process and end product
testing would show instant lots to meet specifications."
HUMAN DRUG CGMP NOTES, VOLUME 05, NUMBER 03 (September 1997)
Motise's Notebook
Policy Questions:
3)
[VIP ID: 4023]
"Does FDA have impurities acceptance limits for cleaning validation and subsequent cleaning
verification?
FDA has always been concerned with the issue of contamination and cross contamination. Such
contamination may include not only carry over from a previous product or residual cleaning solvents, but
also detergents and surfactants.
Except for penicillin, FDA has not established standard acceptance limits for cleaning validation. Due to
the wide variation in both equipment and products produced, it would be unrealistic for the agency to
determine a specific limit. In the CGMP context, however, firms need to establish limits that reflect the
practical capability of their cleaning processes, as well as the specificity of the analytical test method.
We have found that some firms have incorrectly applied as their acceptance limit the 0.1% impurity
identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices.
This application of the 0.1% impurity threshold is inappropriate because the limit is intended for
qualifying impurities that are associated with the manufacturing process or related compounds and not
extraneous impurities caused by cross contamination. It is important that acceptance limits reflect the
capability of the cleaning process.
While we suggest that these factors be considered, relying only on visual examination would not be
scientifically sound."
HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 02 (June 1998)
Motise's Notebook:
POLICY QUESTIONS:
Purely Speaking: (Impurity Issues)
Question 2
[VIP ID: 5906]
"What should investigators look for when inspecting a firm's cleaning validation program?
The objective of cleaning validation is to ensure that a specific cleaning process will consistently clean to
predetermined limits so as to prevent contaminants (product or cleaning process related) from adversely
affecting the safety and quality of the next product manufactured.
As stated in the Guide to Inspections of Validation of Cleaning Processes, determine if firms have a
written, well established and validated cleaning program. Basic steps include the development of a
sensitive, accurate and precise analytical method for the determination of an acceptable limit, something
necessary for any analytical test method developed in conformance with CGMPs. In addition, as
discussed in the guide, determine if firms have and follow specific written procedures as to how cleaning
will be performed, as well as how the cleaning validation will be conducted (including sampling
procedures and analytical methods). Determine if the validation protocol addresses different sampling
surface types, hardest to clean areas, and specific equipment, including utensils. FDA expects the
validation studies will be completed in accordance with written protocols and that the final validation
report will include the appropriate conclusions with management concurrence.
Performing testing of cleaned equipment, in accordance with written procedures, would be consistent
with 21 CFR 211.67(b)."
HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 02 (June 1998)
Motise's Notebook:
POLICY QUESTIONS:
Purely Speaking: (Impurity Issues)
Question 1
[VIP ID: 5905]
"Is testing rinse solution alone enough to support residue determinations for cleaning
validation?
While it is understood that rinse samples are capable of sampling larger surface areas, particularly ones
which are difficult to access, for the purposes of cleaning validation, rinse samples alone would not be
acceptable unless a direct measurement of the residue or contaminant has been made. One
disadvantage of rinse samples is that the residue or contaminant may not be soluble or may adhere to
the equipment. Some firms use both swab samples, where feasible, and rinse samples during the
course of their cleaning validation.
For routine equipment cleaning after validation, some firms may be able to justify use of rinse samples to
demonstrate the process continues to consistently clean the equipment. FDA has compared rinse
samples to that of a "dirty pot analogy." When evaluating the cleaning of a dirty pot, the rinse water is not
what is looked at to see if the pot is clean.
The purpose of cleaning validation is to demonstrate that a particular cleaning process will consistently
clean the equipment to a predetermined limit; the sampling and analytical test methods should be
scientifically sound and provide adequate scientific rationale to support the validation."
HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 04 (December 1998)
Motise's Notebook
POLICY QUESTIONS:
Question 3
[VIP ID: 5982]
"Can a facility that produced penicillin dosage forms be decontaminated and renovated for
production of non-penicillin solid dosage forms provided there is no further penicillin production
in the renovated facility?
Yes. However, the decontamination process is extremely difficult and we are unaware of any firm that
has successfully decontaminated a penicillin facility and converted it to production of non-penicillin
products.
Note that at section 211.176 the CGMP regulations require that if a reasonable possibility exists that a
non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin
product must be tested for the presence of penicillin and not marketed if detectable levels are found
using the codified method. Such a reasonable possibility may be present where decontamination has not
been conducted effectively. That would put the responsible firm in a position of having to test each and
every lot of non-penicillin product for the presence of penicillin.
In sum, while the CGMP regulations would not prohibit decontamination and conversion, the difficulty of
cleaning up penicillin residues makes the chore daunting."
HUMAN DRUG CGMP NOTES, VOLUME 07, NUMBER 01 (March 1999)
Motise's Notebook
Policy Questions On:
Question 3
[VIP ID: 6005]
Any detectable levels of penicillin residue are considered violative because 21 CFR 211.176 indicates
that a non-penicillin drug product must not be marketed if detectable levels of penicillin are found when
tested according to procedures specified in The Procedures for Detecting and Measuring Penicillin
Contamination in Drugs.
The current analytical standard for demonstrating adequate decontamination of facilities, separation
within the same building, or measurement of cross-contamination is codified at 21 CFR 211.176 and
436.104 and has a limit of detectability of 0.006 PPM (as Penicillin G using S. Lutea) and a violative
detection amount of 0.03 PPM. Note that the latter amount reflects the method's limits with respect to
confidence and reproducibility and does not represent a tolerance level. This analytical methodology is
limited to the detection of Penicillin G and ampicillin in a limited number of products listed in the
referenced method, not including other beta-lactam antibiotics. In situations where this methodology is
not workable, it is the firm's responsibility to develop, validate, and use other methodology with similar
sensitivity."
HUMAN DRUG CGMP NOTES, VOLUME 07, NUMBER 01 (March 1999)
Motise's Notebook
Policy Questions On:
Question 4
[VIP ID: 6006]
The following extracts have been taken from the FDA's "Questions and Answers on Current Good
Manufacturing Practices, Good Guidance Practices, Level 2 Guidance” document. These extracts
supplement the information contained in the previous sections.
“A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy
broth) prepared by filtration through 0.2 micron sterilizing filter. Investigation did not show any
obvious causes. What could be the source of contamination?”
“A firm recently had multiple media fill failures. The media fill runs, simulating the filling process during
production, were conducted inside an isolator. The firm used TSB (non-sterile bulk powder) from a
commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An
investigation was launched to trace the source of contamination. The investigation was not successful in
isolating or recovering the contaminating organism using conventional microbiological techniques,
including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media,
and examination under a microscope. The contaminant was eventually identified to be Acholeplasma
laidlawii by using 16S rRNA gene sequence. The firm subsequently conducted studies to confirm the
presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the
process, but from the media source.
Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane
and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain.
Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in
size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is capable of
penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.). Acholeplasma
laidlawii is known to be associated with animal-derived material, and microbiological media is often from
animal sources. Environmental monitoring of mycoplasma requires selective media (PPLO broth or
agar).
Resolution:
For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter
(note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation). In the
future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier.
(Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.)
The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify
its removal. In this case, a thorough investigation by the firm led to a determination of the cause of the
failure and an appropriate corrective action.
References:
- 21 CFR 211.113: Control of microbiological contamination
- 21 CFR 211.72: Filters
- 21 CFR 211.84(d)(6): Testing and approval or rejection of components, drug product container, and
closures
- Sundaram, S., Eisenhuth, J., Howard, G., Brandwein, H. Application of membrane filtration for removal
of diminutive bioburden organisms in pharmaceutical products and processes. PDA J. Pharm. Sci.
Technol. 1999 Jul-Aug; 53(4): 186-201.
- Kong, F., James, G., Gordon, S., Zekynski, A., Gilbert, G.L. Species-specific PCR for identification of
common contaminant mollicutes in cell culture. Appl. Environ. Microbiol. 2001 Jul; 67(7): 3195-200.
- Murray, P., Baron, E., Pfaller, M., Tenover, F., Yolken, R. Manual of Clinical Microbiology ASM Press,
Sixth Edition.
Contact for further information:
Brenda Uratani, CDER
uratanib@cder.fda.gov”
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES (August 2004)
3
[VIP ID: 190904]
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
EQUIPMENT (May 2005)
2
[VIP ID: 190922]
“Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of
contaminants in evaluating cleaning effectiveness?”
“Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies
have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. In
order for TOC to be functionally suitable, it should first be established that a substantial amount of the
contaminating material(s) is organic and contains carbon that can be oxidized under TOC test
conditions. This is an important exercise because some organic compounds cannot be reliably detected
using TOC.
TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample
testing. In either case, because TOC does not identify or distinguish among different compounds
containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for
comparing with the established limit. Thus, a firm should limit 'background' carbon (i.e., carbon from
sources other than the contaminant being removed) as much as possible. If TOC samples are being
held for long periods of time before analysis, a firm should verify the impact of sample holding time on
accuracy and limit of quantitation.
References:
- 21 CFR 211.67: Equipment cleaning and maintenance.
- 21 CFR 211.160(b): General requirements (Laboratory Controls)
- USP 643 Total Organic Carbon
- Guide to Inspections of Cleaning Validation, 1993
Contact for further information:
Abi D'Sa, CDER
dsaa@cder.fda.gov
Brian Hasselbalch, CDER
hasselbalchb@cder.fda.gov”
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
EQUIPMENT (May 2005)
3
[VIP ID: 190924]
“A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy
broth) prepared by filtration through 0.2 micron sterilizing filter. Investigation did not show any
obvious causes. What could be the source of contamination?”
“A firm recently had multiple media fill failures. The media fill runs, simulating the filling process during
production, were conducted inside an isolator. The firm used TSB (non-sterile bulk powder) from a
commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An
investigation was launched to trace the source of contamination. The investigation was not successful in
isolating or recovering the contaminating organism using conventional microbiological techniques,
including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media,
and examination under a microscope. The contaminant was eventually identified to be Acholeplasma
laidlawii by using 16S rRNA gene sequence. The firm subsequently conducted studies to confirm the
presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the
process, but from the media source.
Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane
and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain.
Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in
size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is capable of
penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.). Acholeplasma
laidlawii is known to be associated with animal-derived material, and microbiological media is often from
animal sources. Environmental monitoring of mycoplasma requires selective media (PPLO broth or
agar).
Resolution:
For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter
(note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation). In the
future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier.
(Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.)
The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify
its removal. In this case, a thorough investigation by the firm led to a determination of the cause of the
failure and an appropriate corrective action.
References:
- 21 CFR 211.113: Control of microbiological contamination
- 21 CFR 211.72: Filters
- 21 CFR 211.84(d)(6): Testing and approval or rejection of components, drug product container, and
closures
- Sundaram, S., Eisenhuth, J., Howard, G., Brandwein, H. Application of membrane filtration for removal
of diminutive bioburden organisms in pharmaceutical products and processes. PDA J. Pharm. Sci.
Technol. 1999 Jul-Aug; 53(4): 186-201.
- Kong, F., James, G., Gordon, S., Zekynski, A., Gilbert, G.L. Species-specific PCR for identification of
common contaminant mollicutes in cell culture. Appl. Environ. Microbiol. 2001 Jul; 67(7): 3195-200.
- Murray, P., Baron, E., Pfaller, M., Tenover, F., Yolken, R. Manual of Clinical Microbiology ASM Press,
Sixth Edition.
Contact for further information:
renda Uratani, CDER
uratanib@cder.fda.gov”
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
EQUIPMENT (May 2005)
4
[VIP ID: 190926]
“Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of
contaminants in evaluating cleaning effectiveness?”
“Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies
have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning
validation. But in order for TOC to be functionally suitable, it should first be established that a substantial
amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC
test conditions. This is not a trivial exercise because we know that some organic compounds cannot be
reliably detected using TOC.
TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample
testing. In either case, because TOC does not identify or distinguish among different compounds
containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for
comparing with the established limit. Thus, a firm should limit 'background' carbon (i.e., carbon from
sources other than the contaminant being removed) as much as possible. The established limit, or the
amount of residue detected for comparison to the specification, should correct for the target material's
composition of carbon. As for any cleaning method, recovery studies are necessary (211.160(b)). If
TOC samples are being held for long periods of time before analysis, a firm should verify the impact of
sample holding time on accuracy and limit of quantitation.
References:
- 21 CFR 211.67: Equipment cleaning and maintenance.
- 21 CFR 211.160(b): General requirements (Laboratory Controls)
- USP <643> Total Organic Carbon
- Guide to Inspections of Cleaning Validation, 1993
Contact for further information:
Abi D'Sa, CDER
albinus.dsa@fda.hhs.gov
Brian Hasselbalch, CDER
brian.hasselbalch@fda.hhs.gov”
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
LABORATORY CONTROLS (September 2006)
4
[VIP ID: 190956]
“Would a paramagnetic or laser oxygen analyzer be able to detect all possible contaminants or
impurities in a medical gas?”
“No. Although, paramagnetic and laser oxygen analyzers are very accurate and reliable when calibrated
correctly, these types of analyzers can only detect the identification and strength of oxygen. They are
unable to detect contaminants or impurities that may be present, such as hydrocarbons or arsenic
compounds. According to the USP General Notices, Foreign Substances and Impurities section, "it is
manifestly impossible to include in each monograph a test for every impurity, contaminant, or adulterant
that might be present." The USP monograph test for oxygen does not include an impurity screen and
other analyzers may need to be used. For example, assays for hydrocarbon impurities are routinely
conducted during the oxygen manufacturing process even though the USP does not list hydrocarbons
as an impurity. Also, alternative methods may be needed to test high-pressure cylinders for cleaning
solution residues.
References:
- 21 CFR 211.160: General requirements (Laboratory Controls)
- 21 CFR 211.165: Testing and release for distribution
- United States Pharmacopoeia
Contact for further information:
Duane Sylvia, CDER
duane.sylvia@fda.hhs.gov”
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
LABORATORY CONTROLS (September 2006)
5
[VIP ID: 190958]
“Do the CGMPs require a firm to retain the equipment status identification labels with the batch
record or other file? Assuming each major piece of equipment has a unique "Cleaning and Use
Log" that is adequately retained, is it acceptable to discard these 'quick reference' equipment
labels?”
“The CGMP regulations for finished pharmaceuticals require the retention of cleaning and use logs for
non-dedicated equipment, but no similar requirement exists for retaining what are intended to be "quick
reference" or temporary status labels. Examples of these kinds of status labels include "mixing lot ###";
"clean, ready for use as of d/M/y"; "not clean." We see no value in the retention of such labels in addition
to the required equipment log or batch record documentation. The labels serve a valuable, temporary
purpose of positively identifying the current status of equipment and the material under process. Any
status label should be correct, legible, readily visible, and associated with the correct piece of equipment.
The information on the temporary status label should correspond with the information recorded in the
equipment cleaning and use log, or the previous batch record for non-dedicated equipment.
Labels are merely one way to display temporary status information about a piece of equipment. It is
considered acceptable practice to display temporary equipment status information on dry-erase boards
or chalkboards. And it would be appropriate for an FDA investigator to verify that the information on a
temporary status label is consistent with the log.
References:
- 21 CFR 211.182: Equipment cleaning and use log
- 21 CFR 211.105: Equipment identification
Contact for further information:
Brian Hasselbalch, CDER
hasselbalchb@cder.fda.gov”
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
PRODUCTION AND PROCESS CONTROLS (May 2005)
1
[VIP ID: 190970]
“A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy
broth) prepared by filtration through 0.2 micron sterilizing filter. Investigation did not show any
obvious causes. What could be the source of contamination?”
“A firm recently had multiple media fill failures. The media fill runs, simulating the filling process during
production, were conducted inside an isolator. The firm used TSB (non-sterile bulk powder) from a
commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An
investigation was launched to trace the source of contamination. The investigation was not successful in
isolating or recovering the contaminating organism using conventional microbiological techniques,
including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media,
and examination under a microscope. The contaminant was eventually identified to be Acholeplasma
laidlawii by using 16S rRNA gene sequence. The firm subsequently conducted studies to confirm the
presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the
process, but from the media source.
Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane
and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain.
Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in
size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is capable of
penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.). Acholeplasma
laidlawii is known to be associated with animal-derived material, and microbiological media is often from
animal sources. Environmental monitoring of mycoplasma requires selective media (PPLO broth or
agar).
Resolution:
For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter
(note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation). In the
future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier.
(Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.)
The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify
its removal. In this case, a thorough investigation by the firm led to a determination of the cause of the
failure and an appropriate corrective action.
References:
- 21 CFR 211.113: Control of microbiological contamination
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES,
LEVEL 2 GUIDANCE
PRODUCTION AND PROCESS CONTROLS (May 2005)
3
[VIP ID: 190974]
In addition to the more specific points for consideration generated as part of the review the following
general notes were also compiled:
1. Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a
cleaning process has been validated. This would be particularly true for the bulk drug substance
manufacturer where reactors and centrifuges and piping between such large equipment can be
sampled only using rinse solution samples. Any indirect test method must have been shown to
correlate with the condition of the equipment.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
IV. Evaluation of Cleaning Validation
4. Sampling
c. Routine Production In-Process Control Monitoring -
[VIP ID: 1347]
“Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process
has been validated. This would be particularly true for the bulk drug substance manufacturer where reactors and
centrifuges and piping between such large equipment can be sampled only using rinse solution samples. Any
indirect test method must have been shown to correlate with the condition of the equipment.”
2. Cleaning methods for sterile manufacturing areas should be evaluated when the rooms are not in
use and microbial counts are noted.
Selected FDA 483 Observations (September 1999)
Sterile Product Manufacture
[VIP ID: 8150]
“Cleaning methods for sterile manufacturing areas should be evaluated when the rooms are not in use and
microbial counts are noticed.”
3. The effectiveness of the production disinfection procedure for equipment and other articles entering
the sterile core should be demonstrated for all types of equipment and other articles entering the
sterile core.
Selected FDA 483 Observations (January 2000)
Sterile Product Manufacture
[VIP ID: 14390]
“The effectiveness of the production disinfection procedure for equipment and other articles entering the sterile
core should be demonstrated for all types of equipment and other articles entering the sterile core.”
• Cleaning and sanitising agents including those used on work surfaces, equipment, walls and floors
in clean rooms should be studied to assure effectiveness against micro-organisms.
Selected FDA 483 Observations (April 2000)
Medical Device Manufacture
[VIP ID: 15490]
“Cleaning and sanitizing agents including those used on work surfaces, equipment, walls and floors in clean rooms
should be studied to assure effectiveness against micro-organisms.”
4. The frequency for sweeping and sanitising floors in warehouses, drying oven rooms, production
hallways, and loading docks etc. should be established.
Selected FDA 483 Observations (May 2003)
Product Manufacture
[VIP ID: 15910]
“The frequency for sweeping and sanitizing floors in warehouses, drying oven rooms, production hallways, and
loading docks etc. should be established.”
6. The use of formaldehyde is a much less desirable method of sterilisation of equipment. It is not
used in the United States, primarily because of residue levels in both the environment and in the
product. A major problem with formaldehyde is its removal from piping and surfaces. In the
inspection of a facility utilising formaldehyde as a sterilant, pay particular attention to the validation
of the cleaning process. The indirect testing of product or drug substance to demonstrate the
absence of formaldehyde levels in a system is unacceptable. As discussed in the Cleaning
Validation Guide, there should be some direct measure or determination of the absence of
formaldehyde. Since contamination in a system and in a substance is not going to be uniform,
merely testing the substance as a means of validating the absence of formaldehyde is
unacceptable. Key surfaces should be sampled directly for residual formaldehyde.
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994)
V. EQUIPMENT
(para 3)
[VIP ID: 2030]
“The use of formaldehyde is a much less desirable method of sterilization of equipment. It is not used in the United
States, primarily because of residue levels in both the environment and in the product. A major problem with
formaldehyde is its removal from piping and surfaces. In the inspection of a facility utilizing formaldehyde as a
sterilant, pay particular attention to the validation of the cleaning process. The indirect testing of product or drug
substance to demonstrate the absence of formaldehyde levels in a system is unacceptable. As discussed in the
Cleaning Validation Guide, there should be some direct measure or determination of the absence of formaldehyde.
Since contamination in a system and in a substance is not going to be uniform, merely testing the substance as a
means of validating the absence of formaldehyde is unacceptable. Key surfaces should be sampled directly for
residual formaldehyde.”
8. A change in the primary analytical assay used in cleaning validation studies, from one to another,
should be documented under formal change control requirements, and the procedures should
include a rationale for the change in methods.
Selected FDA 483 Observations (November 2006)
Active Pharmaceutical Ingredient Manufacture
[VIP ID: 194210]
“A change in the primary analytical assay used in cleaning validation studies, from one to another, should be
documented under formal change control requirements, and the procedures should include a rationale for the
change in methods.”
9. Spreadsheets used to calculate linearity, percent recovery, and final assay results for cleaning
validation should be validated and the data transcribed from chromatographs to the spreadsheets
should be checked for accuracy.
Selected FDA 483 Observations (October 2002)
Laboratories
[VIP ID: 51150]
“Spreadsheets used to calculate linearity, percent recovery, and final assay results for cleaning validation should be
validated and the data transcribed from chromatographs to the spreadsheets should be checked for accuracy.”
11. Where a proposed construction project may affect ongoing production, a protocol should be
developed to include increased cleaning of areas affected by the construction.
Selected FDA 483 Observations (February 2005)
Sterile Product Manufacture
[VIP ID: 138140]
“Where a proposed construction project may affect ongoing production, a protocol should be developed to include:
d. Increased cleaning of areas affected by the construction.”
7. REFERENCES
All the references in blue have been extracted from either the regulations, guidance documents and
warning letters freely available from the FDA’s web site at www.fda.gov, or from FDA 483 Inspectional
Observations and Establishment Inspection Reports.
The references in red have been extracted from either the European Commission Directives and the
Eudralex, Volume 4 - Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice
and Annexes, which are freely available and can be downloaded from the Eudralex web site at
www.ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev4.htm, or from PIC/S (Pharmaceutical
Inspection Convention/Pharmaceutical Inspection Co-operation Scheme) publications, most of which
can be downloaded free from their web site at www.picscheme.org.
The references in green have been extracted from International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, which are
freely downloadable from the ICH web site at www.ich.org/cache/compo/276-254-1.html.
Bound copies of this guidance document can be purchased directly from Validation in Partnership
Limited, if required. For details of price and delivery, or to find out more about us and the services we
offer please visit the ViP Web Site: www.ViPltd.co.uk or contact us directly at the address below.