54
Japanese Regulatory Requirements
SECTION 1: PHARMACEUTICAL ADMINISTRATION
AND REGULATIONS IN JAPAN
Tsuguo Sasaki
Musashimurayama, Tokyo, Japan
Fumi Yamamoto
Ministry of Health, Labor and Welfare (MHLW), Chiyoda,
Tokyo, Japan
Pharmaceutical administration in Japan is based on
various laws and regulations, consisting mainly of (i)
Pharmaceutical Affairs Law, (ii) Pharmacists Law, (iii)
Organization for Pharmaceutical Safety and Research
Law, (iv) Blood Collection and Blood Donation Services
Control Law, (v) Poisonous and Deleterious Substances
Control Law, (vi) Narcotic and Psychotropic Control Law,
(vii) Cannabis Control Law, (viii) Opium Law, and (ix)
Stimulants Control Law. For the enforcement and manage-
ment of these laws, detailed regulations are prepared by
the government in the form of ministerial ordinances and
notices, such as the Enforcement Ordinance and the
Enforcement Regulations of the Pharmaceutical Affairs
Law, and notications are issued by the Director General
of the Bureau or by the directors in charge of the Division
in the MHLW.
Pharmaceutical Affairs Law
The Pharmaceutical Affairs Law is intended to improve
public health through regulations required to assure the
quality, efcacy, and safety of drugs, quasi-drugs,
cosmetics and medical devices, and through measures
to promote R&D of drugs and medical devices that are
especially essential for health care. Modern pharma-
ceutical legislation originated in Japan with the
enactment of the Regulations on Handling and Sales of
Medicines in 1889. The Pharmaceutical Affairs Law was
Abbreviations used in this chapter: ADR, adverse drug reaction; API,
active pharmaceutical ingredient; ATCC, American Type Culture
Collection; BI, biological indicator; CFU, colony-forming units; CJD,
CreutzfeldtJakob disease; EN, European standards; EO, ethylene
oxide; EU-GMP, European Union good manufacturing practice;
FDA, Food and Drug Administration; GCP, good clinical practice;
GLP, good laboratory practice; GMP, good manufacturing
practice; HEPA, high-efciency particulate air; ICH, International
Conference on Harmonization; IFO, Institute for Fermentation,
Osaka, Japan; ISO, International Organization for Standardization;
JCM, Japan Collection of Microorganisms; JP, Japanese Pharmacopoeia;
MHLW, Ministry of Health Labor and Welfare; PAFSC, Pharma-
ceutical Affairs and Food Sanitation Council; PFSB, Pharmaceutical
and Food Safety Bureau; PMDA, Pharmaceuticals and Medical
Devices Agency; PS, pure steam; RO, reverse osmosis; SAL, sterility
assurance level; SOP, standard operating procedure; TOC, total
oxidizable carbon; UF, ultraltration; UF water, ultraltered water;
USP, United States Pharmacopeia; WFI, water for injection; WHO-
GMP, World Health Organization-Good Manufacturing Practice.
enacted in 1943 and has been revised several times since
then. The current Pharmaceutical Affairs Law is the result
of complete revisions in 1948 and 1960. Subsequent
revisions have included (i) the reexamination of new
drugs, the reevaluation of drugs, notication of clinical
study protocols, and items required for sponsoring
clinical studies in 1979, (ii) direct manufacturing approval
applications by foreign pharmaceutical manufacturers,
and the transfer of manufacturing or import approvals
in 1983, and (iii) promotion of R&D of orphan drugs and
priority reviews for such drugs in 1993.
In 2002, the Pharmaceutical Affairs Law was
revised based on demands for augmentation of safety
assurance in keeping with the age of biotechnology and
genomics, augmentation of postmarketing surveillance
policies, revision of the approval and licensing system
(clarication of the responsibility of companies for safety
measures and revision of the manufacturing approval
system in accordance with international coordination)
and a radical revision of safety policies for medical
devices. The revised Pharmaceutical Affairs Law was
partly enforced in 2003 and the remaining will be
enforced in 2005. The main revisions concerning drugs
are summarized in the following sections.
Provisions Enforced in July 2003
1. Exemptions for Biological Products. Regulations to be
applied to biological products were reinforced to
prevent CJD associated with dried dura, HIV infec-
tion through blood transfusion, and other infections
with unknown viruses. Biological products manufac-
tured using biological materials derived from human
and animal tissues and cells are expected to be
clinically valuable, and the development of new
biological products will be further promoted in-line
with the progress of medical science such as genomic
research and regenerative medicine. Since biomater-
ials tend to have a high risk of contamination due to
infectious viruses or other factors, safety assurance
policies have been integrated to control the entire
process from raw material collection to manufacture
and postmarketing surveillance to ensure the safety
of biological products.
2. ADR reporting system by medical institutions, etc.
Regulations to be applied to safety measures were
reinforced by specifying reporting of ADRs and
infections by medical institutions and drug stores
required by the Pharmaceutical Affairs Law.
3. Matters related to clinical trials. With the purpose of
widely utilizing ndings and achievements of clinical
research, trials intended for approval application
among those initiated by investigators or medical
institutions were given the status of clinical trials as
dened in the Pharmaceutical Affairs Law, and use of
unapproved drugs or medical devices have been
684 X: GENERAL TOPICS
permitted. Clinical research initiated by medical
institutions or physicians complying with the GCP
for the purpose of approval applications can be
conducted using unapproved drugs or medical
devices under the clinical trial notication system.
Provisions to be Enforced in April 2004
1. Matters related to the requirements for licensing manu-
facturing/distribution businesses and manufacturing
business. The current approval and licensing system
has been reviewed to further strengthen postmar-
keting surveillance of drugs in keeping with the
changing industrial structure and business system
(e.g., company split up, complete contracted manu-
facture, and foreign contracted manufacture), and to
promote international coordination. Previously,
licenses were issued for individual manufacturing
facilities owned by the approval holder under the
premise that drugs and medical devices are manu-
factured by the approval holder itself. The new
system separates primary business (manufacturing
and distribution: business of delivering and selling
products on the market) and manufacturing business
(manufacturing) and grants manufacturing/distribu-
tion approvals under the requirements that product
quality must be well controlled and postmarketing
safety measures must be assured.
2. Approvals and regulatory affairs. A manufacturing
approval application for drugs, etc. must be submitted
by the manufacturing/distribution license holder
who is totally responsible for the product to be sold.
Procedures of manufacturing and quality control will
become requirements for approval and, depending on
the type of products, certain supplementary docu-
ments such as risk analysis and conformity to basic
requirements must be attached. It is also one of the
basic requirements that manufacturing facilities are
inspected to assess the manufacturing capacity of the
applicant, i.e., manufacturing method and product
quality, according to GMP prior to the approval.
With an aim to make approval reviews faster and
more efcient, minor changes in approved items
including names, dosage, manufacturing method,
specications of product quality, and indications are
approved by the notication system instead of the
current approval license system.
3. Master le systems for drugs, etc. Detailed information
and data concerning manufacturing method of the
drug substance and other raw materials are the
intellectual property of the industry. To protect such
property with respect to the manufacturer or manufac-
turer/distributor of a nal drug product and to
simplify regulatory reviews by the agency, the
master le system is to be introduced to permit the
manufacturer of the drug substance to register the
name, manufacturing method, pharmaceutical prop-
erties, quality, etc. of drug substance.
Approval and Licensing of Pharmaceutical Products
Any person who intends to manufacture or import drugs
in Japan shall obtain an approval from the Minister of
Health, Labor and Welfare or prefectural governor. For
drugs such as radiopharmaceuticals, biological products,
and blood-typing antibodies, which require special
precautions with respect to public health and sanitation
based on Article 42 of the Pharmaceutical Affairs Law, the
Minister grants the license. Before granting the approval,
the central or prefectural authorities examine, on the basis
of data submitted by the applicant, each product under
application for details such as the name, ingredients and
quantities, administration and dosage, indications, and
adverse reactions. From April 2005, manufacturing
(import) approvals has changed to manufacturing and
distribution approvals and manufacturing (import)
licenses has changed to marketing licenses as specied
in the Pharmaceutical Affairs Law revised in 2003.
Marketing licenses are issued after assuring that the
applicant is able to manufacture or distribute the
approved drugs, e.g., whether manufacturing or business
facilities of the applicant have sufcient structures and
equipment, manufacturing and quality control systems
and human resources to properly deal with the
approved drugs.
Approval Reviews of Pharmaceutical Products
Application forms for approval to distribute drugs are
usually submitted to the prefectural authorities who
forward them to the MHLW. When forms for new
drugs are received by the PMDA for evaluation, a
reliability review of the application data as well as GLP
and GCP compliance reviews are undertaken by the
PMDA. When the reliability and compliance of the data
are conrmed, a detailed review is undertaken by a team
of experts in the eld concerned at the PMDA, and the
team prepares a team review report. A new system,
consisting of meetings of specialists, has been introduced
for review and evaluation of new drug applications.
These meetings, consisting of team reviewers and
medical experts, focus on the discussion of key issues.
The evaluation process followed by the PMDA is as
follows:
1. Interview (presentation, inquiries, and checking)
2. Team review
3. Inquiries and checking
4. Report (1)
5. Specialists meeting (includes at least three clinical
experts)
6. Hearing (main agenda items and specialist committee
participants notied to the applicant two weeks prior
to meeting; presentation)
7. Follow-up specialist meeting
8. Report (2)
9. Report to the Evaluation and Licensing Division,
PFSB, and MHLW
Finally, a report is submitted to the Committee on
New Drugs of the PAFSC for review and discussion as
required on the basis of the review report and sent to the
MHLW where the Minister grants approval to the new
drug (Fig. 1). In reviews of new drugs with new active
ingredients, drug samples are requested for special
reviews, and the specications and testing methods are
usually checked by the National Institute of Health
Sciences or by the National Institute of Infectious
Diseases in the case of biological products.
Drug approval reviews are normally processed in
the order the application forms are received, but with this
 54: JAPANESE REGULATORY REQUIREMENTS 685

Outside
Applicant PMDA
experts

Interviews: Team Reviews Designation,

Applicant and Review Experts Reliability Consultations

- Inquiries and Confirmation Reviews

from PMDA
Advice
- Presentations and Replies
from Applicant

Review Report (1)

Review Experts + Outside Experts

Review Expert - Discussion on Main Problems, Coordination
Conference I of Opinions
- Paper Discussions also Held

Summary of Main Problems

- Meeting for Explanation (Presentation) by

Applicant
Interview Applicant and Review Experts - Investigation of Main Problems
Review
Meeting Applicants Experts and Outside Experts - Meeting Presided Over by Person in Charge of
Review (or General Review Supervisor)
- Meeting may be Held Twice.

Review Expert Review Experts and Outside Experts

Conference II - Held Following Interview Review Meeting

Review Report (2)

Review Results
(Review Results Notification)

Inquiries

Approval Pharmaceutical
MHLW Affairs and Food
Replies Sanitation Council

Figure 1 Flowchart of approval review.

system, applications are reviewed on a priority basis for
drugs, which have been designated as orphan drugs and
other drugs, which are considered to be especially
important from a medical standpoint. The latter drugs
include those indicated for serious diseases and those
which are particularly excellent medically with respect to
efcacy and safety when compared with existing drugs.
Historical Background of GMP
Proper control at the stage of drug manufacture is
essential so that drugs can be supplied to patients with
good quality. This means that the manufacturers and the
buildings and facilities in the manufacturing plants must
be appropriate so that drugs based on the approvals can
be produced. The manufacturing process as a whole must
be controlled on the basis of scientic principles and it is
also necessary to assure the quality of drugs manufac-
tured by taking measures to prevent errors during
processing. Since a recommendation to introduce GMP
was issued by WHO in July 1969, various countries have
passed laws concerning control procedures essential for
the manufacture of drugs. In Japan, Standards for Manu-
facturing Control and Quality Control (GMP) were issued
in September 1974 and they were enforced from April
1976 with some exceptions. With the partial revision of the
Pharmaceutical Affairs Law in October 1979, the GMP
686 X: GENERAL TOPICS
became legally binding. The control part of the GMP is
specied in Drug Manufacturing and Quality Control
Regulations (called GMP software) in August 1980,
and the parts concerning buildings and facilities are
specied in the revision of the Regulations for Buildings
and Facilities for Pharmacies, etc. (called GMP hard-
ware) in 1980 based on Article 13 of the Pharmaceutical
Affairs Law. Thereafter, provisions related to validation,
recall, self-inspections, and education and training were
added and the revised Regulations for Manufacturing
Control and Quality Control of Drugs (called GMP
software) and Regulations for Buildings and Facilities
for Pharmacies, etc. (called GMP hardware) were
issued and came into effect from April 1994. Provisions
required to assure the quality of biological products,
including prevention of contamination by microorgan-
isms, were added to the GMP software in 1997 and to the
GMP hardware in 1999 since biological products require
handling of animals and microorganisms in the manu-
facturing process and a high level of control in accordance
with the features of individual products such as util-
ization of biological reactions. GMP software was
revised to apply to some quasi-drugs in March 1999. To
eliminate the risk of spreading infections from cell- and
tissue-derived drugs and medical devices, requirements
were added to both GMP software and GMP hardware in
March 2001. The GMP was drastically revised in
December 2004. In particular, the requirements for manu-
facturing control and quality control (so-called GMP
software) were revised to contain items on manufacturing
control and quality control specic to drug substances,
sterile drug products, or biological products. In addition,
the manufacturer is required to retain records on modi-
cations and deviations from SOPs. These SOPs which are
to be retained at each manufacturing facility are listed in
Table 1.
Table 1 SOPs and Actual Operating Procedures Based on
SOPs to be Retained at Each Manufacturing Facility
1. Hygiene control standards specifying procedures for maintaining
cleanness of buildings and facilities, health of personnel at
manufacturing plants, and other related matters; manufacturing
control standards specifying procedures for storage of nal
products, control of manufacturing processes, and other related
matters; and quality control standards specifying procedures for
sample collection, assessment criteria for interpretation of test
results, and other related matters
2. The following SOPs must be retained at each manufacturing facility
in order to implement manufacturing and quality control properly
and effectively
a. Procedures for the management of shipment of products from a
manufacturing site
b. Procedures for validation
c. Procedures for the management of SOP modications
d. Procedures for the management of deviations from SOPs
e. Procedures for the management of information on quality and for
handling poor quality products
f. Procedures for product recall
g. Procedures for self-inspections
h. Procedures for education and training
i. Procedures for archival storage of documents and records
j. Other procedures necessary for the proper and effective
implementation of manufacturing and quality control
Validation
It has been a long time since validation was introduced in
the pharmaceutical industry. The U.S. FDA started evalu-
ation and discussion on the need for validation in 1970s
and issued the Guideline on General Principles of Process
Validation in 1987. Later, validation was specied as one
of the requirements for approval in Europe and Japan.
Various guidelines and manuals have been published for
implementation, and pharmaceutical companies
developed and standardized methodology for validation.
The concept and scope of validation have varied with
time and currently validation has been extended to risk
management. Validation and the GMP in Japan are
concepts imported from the United States; however, it is
an important issue in ICH and ISO and therefore has been
specied as one of the requirements for approval from a
global viewpoint.
Validation is part of GMP and a tool for achieving
stable manufacture of high-quality pharmaceutical
products. The Requirements for Manufacturing Control
and Quality Control Methods in Pharmaceutical Plants
(GMP software specications) species that buildings,
facilities, and manufacturing procedures, processes, and
quality control methods of manufacturing plants must be
properly validated and documented to lead to expected
results. Detailed procedures for the implementation of
validation were specied in a number of ofcial notica-
tions including an ordinance Standard Methods of
Validation issued in 1995 and enforced in 1996. Validation
plays an important role in securing the quality of medical
products since its introduction as a legal system according
to the Pharmaceutical Affairs Law in 1996. Most recently,
Standard Methods of Validation was partly revised in 2000
(Table 2).
Article 13 of the GMP software, which was revised
in 2004, requires validation be performed in cases where
(i) a new medical product is manufactured at a certain
manufacturing plant, (ii) modications of manufacturing
method have a major inuence on the quality of medical
products, or (iii) validation is considered to be necessary
for proper conduct of manufacturing and quality control.
The GMP software also requires the manufacturer (i) to
establish a system of reporting plans and results of
validation in writing to the quality control section, (ii) to
take necessary measures when results of validation
indicate the necessity of improvement in manufacturing
and quality control, and (iii) to record and preserve
outcomes of measures taken in the archives.
In the revised Pharmaceutical Affairs Law, manu-
facturing (import) approvals are scheduled to be replaced
by manufacturing/distribution approvals and the
Table 2 History of Validation in Japan
1993: GMP software was specied as part of the requirements for
manufacturing licensing
1994: GMP software specications were dened
1995: Standard Methods of Validation were specied
1996: Standard Methods of Validation were enforced by law
2000: Standard Methods of Validation were revised
2003: The Enforcement Ordinance of the Pharmaceutical Affairs Law
was issued
2004: GMP was radically revised
2005: The revised Pharmaceutical Affairs Law was enforced

Table 3 Enforcement Requirements for Validation Standards
Status of approved products
Products which have been licensed or which are to be given a
manufacturing license (including license renewal) or subject to
product addition (change) in the period from the date of issue of this
notication until March 31, 1996, so far as they are intended for
continued manufacture on and after April 1, 1996, shall be
subjected to concurrent validation, revalidation and retrospective
validation shown in Tables 4 and 5 (below) of the Validation
Standards, in compliance with the following requirements
1. Concurrent validation
Placing importance on the fact that the prospective validation has
not been conducted yet, an early conrmation shall be made on
three lots of products as directed in the conrmation at an actual
production scale. In case of a product which is not to be
manufactured until a manufacturing license renewal, validation
items shall be established with reference to a past record of
production of similar drugs and entered in the operating procedures
for validation
2. Revalidation
a. Revalidation for changes
Revalidation for changes shall be conducted in accordance with
Table 2 in the case of a change in raw materials, labeling and
packaging materials, procedures, manufacturing process and
buildings and facilities made on and after April 1, 1996, so long as
the change may affect the quality of drugs
b. Regular revalidation
If a trend analysis is impossible due to inadequate data from the
concurrent and the retrospective validation, then the items for
validation shall be mentioned in the operating procedures for
validation
3. Retrospective validation
If data are inadequate for statistical analysis, then the procedures
to collect data shall be described in the operating procedures for
validation so that the validation is conducted on collection of
adequate data
Standard Methods of Validation may be revised. Major
items of the current Standard Methods of Validation are
summarized in Tables 35.
SECTION 2: JAPANESE APPROACH TO VALIDATION
Toshiaki Nishihata and
Tsutomu Hinomoto
Santen Pharmaceutical Co., Ltd., Higashiyodogawa,
Osaka, Japan
Aseptic Processing
Interpretation for the manufacturing of sterile drug
products by aseptic processing is described in the
General Information section in the JP XV. The description
has been prepared in light of the harmonization of the
USP, EU-GMP, and WHO-GMP. As more detailed and
specic explanation of the practice has been requested for
operation, the Manual of Manufacturing Sterile Drug
Products by Aseptic Processing (guideline) was
published in April 2006, incorporating as a basic
concept the General Information in JP XV and inter-
national harmonization, with the collaboration of a
study group of the MHLW Health Science Study.
54: JAPANESE REGULATORY REQUIREMENTS 687
Including those who export their drug products to
Europe and the United States, many manufacturers in
Japan who produce sterile drug products by aseptic
processing have actually been implementing the harmo-
nized practices in-line with the content of the guideline.
Therefore, this section provides a concise summary of the
actual practice in Japan based on the draft guideline.
The basic concept of the validation of aseptic proces-
sing for manufacturing sterile drug products is that the
manufacturing can be achieved in the amalgamation of
hardware such as building facilities and manufacturing
equipment and software of operation methods and
controls. Qualication of manufacturing environment/e-
quipment and process validation intend to secure the
quality of drug products in their manufacturing processes,
among which the assurance of sterility quality by scientic
method and rationale should be considered as one of the
critical matters for sterile drug products. The manufac-
turing processes of the sterile drug products produced by
aseptic processing involve various contamination factors
that cannot be assured during process development stages
and/or designing stages of equipment and operational
procedures, and thus qualication and validation need to
be planned and implemented as an overall system of the
production site. Aseptic processing such as sterilization
and lling, maintenance of air classication in manufac-
turing environment and contamination risk in the facilities
and equipment and/or manufacturing processes in the
production site should be scientically veried to assure
that contamination has been prevented. It is also a basic
requirement to control manufacturing processes with
validated operational procedures and manufacturing
control parameters.
Facility Design
In a manufacturing facility of sterile drug products
produced by aseptic processing, the manufacturing
areas are dened as clean areas classied into four
grades as shown in Table 6 in accordance to the current
draft Japanese guideline. The manufacturing areas of
sterile drug products are clean areas that are controlled
and maintained within the specied limits of contami-
nation by microorganisms and airborne particles, and
classied into critical processing areas, direct support
areas, and indirect support areas depending on the
nature of the operations being carried out. The classi-
cation of each area is generally specied with the
number of airborne particles of not less than 0.5 mm per
unit volume in the air of the environment.
A critical processing area (Grade A) is a manufac-
turing operation area in which sterilized containers and
closures, raw materials, in-process products and the
surfaces that have direct contact with them are exposed
to the environment. After sterilization by ltration, it is
recommended that the sterile drug products produced by
the series of aseptic processing have all the aseptic
processing from aseptic ltration to cap application
carried out in the critical processing area. Likewise, the
sterile drug products produced by the series of aseptic
operation from the raw materials have all the aseptic
processing from manipulation of the starting materials to
cap application carried out in the critical processing area.
688 X: GENERAL TOPICS

Table 4 Validation Requirements for Renewal of the Manufacturing License

After receipt of manufacturing license, validations to be conducted by the time of renewal of the
manufacturing license
Concurrent
validation Revalidation on change
Routine Facility Calibration of Performance Conrmation at
processing qualication measuring instruments qualication actual production
control for changes for changes for changes scale for changesa
Pharmaceutical Sterility and non- B 6 6 6 6
products and bulk pyrogenicityb
drug substances
Other B 6 6 6 6
propertiesc

Periodic revalidation Retrospective validation

Statistical evaluation of
Facility qualication past manufacturing
when checked for Calibration at Performance control and quality
maintenance meter inspection qualication control results
Pharmaceutical Sterility and non- B B B !
products and bulk pyrogenicityb
drug substances
Other propertiesc B B ! B
Notes: B, essential items; 6, items which may affect the quality of drugs; !, items not required to be reported.
a
For a partial change in manufacturing approval, the following rules shall be followed: (i ) Bulk products shall be manufactured when conrmation is made before
permission of the partial change, (ii ) Products shall be manufactured when conrmation is made after permission of the partial change.
b
Buildings and facilities, procedures, processes, etc. to be checked for sterility and non-pyrogenicity.
c
Buildings and facilities, procedures, processes, etc. to be checked for properties other than sterility and non-pyrogenicity which may affect the quality of drugs.

A direct support area (Grade B) is dened as the
background environment for the critical processing area. It
may be used for the manufacturing operations that require
strict control of microbial and particulate contamination.
Indirect support areas (Grades C and D) may be
where presterilized containers and closures, raw
materials, and in-process products are exposed to the
environment during the processing, and/or where
cleaning of the apparatus and/or instrument for aseptic
processing is carried out.
There are 11 general requirements that must be
considered when designing these clean areas: (i) clean
areas shall be distinctively separated from the one for
full-time occupancy and/or in un-sanitized condition;

Table 5 Examples of Critical Process

Purity and
Dosage form/quality specicity Sterility Content uniformity Dissolution crystal form
Sterile drugs Terminal sterilized Sterilizing process Dissolving process;
preparations mixing/dissolving
process; lling
process
Aseptically processed Aseptic operation; Dissolving process;
preparations ltration process; mixing/dissolving
lling process; process; lling
freeze-drying process
process
Solid preparations Mixing process; Granulation process;
granulation tabletting process
process; tabletting
process; lling
process
Liquid preparations Dissolving process;
mixing/dissolving
process; lling
process
Ointment, Kneading process;
suppository, lling process;
poultices spreading process
Bulk drug substances Final purication
process
Sterile bulk drug Sterilizing process; Final purication
substances aseptic operation process

Table 6 Classication of Clean Area
Category
Aseptic processing area Critical processing area
Direct support area
Indirect support area
ISO classication in parentheses corresponds to the number of particles in the in operation conditions.
(ii) clean areas shall be distinctively dened for each
operation and have adequate space; (iii) clean areas
shall provide HEPA-ltered air to maintain air classi-
cation appropriate for the operation being carried out
and have appropriate pressure differential; (iv) clean
areas shall have positive pressure differential relative
to adjacent rooms of lower air cleanliness. To maintain
each clean area environment, it is important to achieve a
proper airow from areas of higher cleanliness to
adjacent areas of lower cleanliness, i.e., pressure differ-
ential between aseptic processing area and indirect
support area shall be sufcient so as not to cause
inversion and/or backow. Pressure differential of 10
to 15 Pa or more is recommended. Also, in indirect
support area, it is necessary to maintain adequate
pressure differential between the areas of different
classication. The airow in the critical processing
areas shall be unidirectional with sufcient velocity
and uniformity so as to promptly remove airborne
particles out of the zones. To prevent ingress of contami-
nation from adjacent areas (direct support area: Grade
B), there shall be no backow of the air from the
adjacent areas; (v) clean areas shall have no direct
access (excluding emergency exit) to the outdoor eld;
(vi) a system shall be implemented to monitor environ-
mental conditions such as temperature, humidity, and
pressure differential; (vii) clean areas shall be controlled
in the temperature and humidity suitable for the charac-
teristics of the materials and/or products and necessary
for microbial control in the areas; (viii) a layout shall be
considered so that the ow and control of personnel,
products, materials, components and waste are
optimized to minimize the intersection of each ow;
(ix) a system or dened areas shall be determined so as
to prevent mix-up of clean and unclean materials or
sterilized and non-sterilized products; (x) separate and
appropriate facility design shall be determined in the
manipulation of sensitizing substance; and (xi) facilities
shall be designed to facilitate cleaning and maintenance
and receive periodical maintenance checks to secure the
design intent. The guideline should be refereed for
detailed explanations to fulll the basic requirements.
Water Systems
Water used in drug products is a ne solvent widely used
for manufacturing and processing of drug products,
cleaning of containers and equipment and dissolution at
use or testing of the products. However, it can be a source
of impurities and microbial contamination in the drug
products. Especially for manufacturing of sterile drug
products, the water for pharmaceutical purposes, which
54: JAPANESE REGULATORY REQUIREMENTS 689
Maximum permitted number of particles per cubic meter
equal to or above 0.5 mm
Air classication At rest In operation
Grade A (ISO 5) 3,520 3,520
Grade B (ISO 7) 3,520 352,000
Grade C (ISO 8) 352,000 3,520,000
Grade D 3,520,000 Depending on the nature of the
operation being carried out
should be supplied in compliance with the JP speci-
cation of water for pharmaceutical purposes (WFI, sterile
puried water and so on), needs to be selected, retained,
and controlled in accordance to GMP without fail so that
any potential risks of contamination with impurities and
microbial growth, contamination of products, and signi-
cant health hazard or medical accidents can be
eliminated. Based on this standpoint, it is considered
crucial, while supplying water for pharmaceutical
purposes, to systematically establish a water system
facility based on the sufcient design verication of
both hard- and software including preventive measures
of microbial contamination; validatates the system to
assure the constant maintenance, control, and supply of
the water of complying quality; and of assure the
specied quality of water by routine monitoring.
In the basic design phase of the facility of water for
pharmaceutical purposes, buildings and facilities and
procedures or other methods regarding manufacturing
and quality control should be clearly determined in
advance in order to achieve constant production of the
water of complying quality. There are ve fundamental
factors that haveto be considered: (i) the specication of
the water (e.g., WFI), volume and control methods should
be determined before the system is designed; (ii) the
quality of source water, including seasonal variations,
should be known before the system is designed; (iii) the
maximum quantity consumed per second, operating
time, frequency of use, conditions at the point of use
(temperature, number of location, specication of piping)
and so on should be determined to design the facility that
will be capable of producing sufcient quantity and
quality of water; (iv) water system basically employs
circulating line (loop) when chemical disinfection is not
feasible; the design should incorporate disinfection or
sterilization consideration so as to assure microbial
control; and (v) the location of sampling points should
be discussed in the design phase and establish them close
to various water processing equipment where the water
needs to be evaluated for its quality.
Regarding the equipment used for pretreatment of
water for manufacturing drug products, it should be
considered before selecting and/or designing that
contaminants in the feed water should be tested to
produce the water with certain or higher quality desired
in accordance to its intended use to ultimately comply
with requirements, and to maximize the equipments
performance and life duration. In selecting the pretreat-
ment equipment, consideration should be given to the
indication of equipment contamination and cleaning
procedures when contaminated as well as to the
690 X: GENERAL TOPICS
measures to minimize the inuence of the contaminants
components such as iron, manganese, other heavy
metals, free chlorine, organic material, microorganisms,
suspension and colloidal particles (e.g., silicate, complex
silicate, organometallic complex) on the function and life
duration of the equipment.
WFI as water for manufacturing is expected to be of
microbiologically high purity for its intended use, and the
WFI system should be capable of undergoing periodical
sterilization with PS at the temperature no lower than
1218C for a certain amount of time. When PS sterilization is
not feasible due to heat tolerance, disinfection or steriliza-
tion with hot water or a chemical agent needs to be
employed. For WFI processing, distillation, reverse
osmosis, ultraltration and any combination of these are
recommended.
In Japan, pharmaceutical water for sterile drug
products (such as WFI) is expected to be used promptly
after being processed so as to avoid microbial contami-
nation and/or deterioration of chemical components in
the water. However, it is often the case that the quantity
processed and consumed are unbalanced and the water is
generally held in the water tank for the meantime. When
a WFI holding tank is designed and/or used, consider-
ation should be given that (i) the tank is tightly sealed and
have smooth inner surface, (ii) the number of convexity
and opening on the tank surface should be requisite
minimum and as short and few as possible, (iii) the
tank should be of the structure that has no static area of
water, facilitates cleaning inside and drains the water out
completely, (iv) a hydrophobic vent lter of 0.2 mm should
be installed at the vent so as to prevent ingress of
microorganisms and impurities, and (v) in case of disin-
fection with hot water, a system should be added so that
the whole inner surface including the ceiling will be
exposed to the heat.
The water for pharmaceutical purposes held in the
holding tank is distributed to the points of use through
the piping in the water system. As the piping is a sealed
system with relatively small diameter, its inner condition
may be difcult to conrm once installed; it is thus
recommended that the control method and preventive
measures be discussed and determined in the design
developing phase. Recommendations are given to
consider that the piping should be a one-way loop with
a preventive structure of backow and no employment of
by-pass and/or branching tubules as much as possible,
and that in order to prevent microbial and organic
material in WFI, it should be heated to, for instance,
808C or higher (the temperature should be established
based on validation results) and constantly recirculated at
the ow rate of not less than 1.0 m/sec. Valves connecting
the loop and branch should be located as close to the loop
as possible to prevent dead-legs; the distance from the
main pipe should be no longer than 6D in principle and
no longer than 3D as a preferable target. Horizontal pipes
are sloped not less than 1 per 100 to prevent a stagnant
pool of water, and drain outlets should be installed to
facilitate drainage of water as well as a structure to
prevent the backow.
For heat exchangers, double tube or double tube-
sheet design is employed as a method for preventing
contamination by leakage. When other methods such as a
plate design are to be used, it is recommended to always
keep higher pressure on the clean uid side so as not to
cause contamination in the clean uid by cooling vehicle,
and provide gauges to monitor the pressure differential.
Recommendations regarding points of use and
sampling include that when sampling at the point of
use is not feasible, the sampling point should be located
in as much vicinity as possible, and that frequency of
sampling at each sampling point should be determined
considering water quality, quantity consumed, seasonal
variations and other factors.
Valves, gauges, and detectors installed in the water
system need to be of sanitary structure such as dia-
phragm and should have no static area of uid or dead
section. In order to ensure timely monitoring of the
chemical quality of the water, installation of a TOC
gauge (a model capable of measuring conductivity at
the same time will be preferable) in the line is desirable.
As for setting up the detector, it is recommended to select
a spot where the water quality would be regionally the
worst in the piping system.
Pumps should be of sanitary structure and be
capable of sealing off to prevent contamination. Hot
water disinfection and/or PS sterilization should be
taken into consideration.
Environmental Monitoring/Product Bioburden
Environmental monitoring mainly intends to maintain
the cleanliness in the manufacturing environment
provided for sterile drug products, in that the microbial
and particulate counts are controlled so as not to exceed
the levels required for aseptic processing areas and
indirect support areas, that any sign of deterioration in
the environment is anticipated to prevent contamination
to products, and that the efciency of sanitization, decon-
tamination and disinfection activities for maintenance of
the cleanliness is continuously evaluated. Environmental
monitoring has two major aspects: microbiological
control and particle control. The purpose of microbiolo-
gical control is to scientically estimate the bioburden of
the environment that it intends not to identify all of the
microorganisms possibly existing in the environment but
to assure that the sterile drug products have been
manufactured under properly controlled conditions and
to implement any processing (e.g., disinfection) as appro-
priate to maintain such environment. Monitoring will be
conducted for microorganisms and airborne particles,
and target particles are dened as airborne particles of
not less than 0.5 mm. However, for more sufcient
environmental monitoring, other particle size (e.g.,
5 mm) may be included as appropriate. Target micro-
organisms are dened as bacteria and fungus and
include those of airborne and surface of the wall, oor,
xtures and manufacturing equipment, and personnel
garments.
Environmental monitoring is conducted in critical
processing areas (Grade A) and direct support areas
(Grade B) in the aseptic processing areas. Indirect
support areas (Grades C and D) adjacent to the aseptic
processing areas may be included as appropriate.
Table 7 shows the frequency of environmental
monitoring. As contamination risk of sterile drug
products may vary depending on the type and volume
of the drug products to be manufactured as well as the
 54: JAPANESE REGULATORY REQUIREMENTS 691

Table 7 Frequencies of Microbiological and Particle Monitoring

Microorganisms Particles
Surface Surface
Airborne microorganisms microorganisms
Area level microorganisms (equipment) (personnel) Processing Non-processing
Grade A Every shift At completion of each Every shift During aseptic Per day
processing operation processing
Grade B Every shift At completion of each Per working day During aseptic Per day
processing operation processing
Grade C As appropriate As appropriate As appropriate Per month Per month
Grade D As appropriate As appropriate As appropriate As appropriate As appropriate

environmental equipment such as air handling system, a
monitoring program should be prepared and
implemented according to the need and as appropriate.
It is also recommended that the monitoring frequency in
Grades C and D area, the indirect support areas, be
determined in accordance to the process or operations
being carried out. Recommended alert and action limits
of microbiological monitoring are shown in Table 8.
Process Simulations
Sterile drug products may be manufactured through a
single or several sterilization processes or a combination
of sterilized components; an aseptic lling process is one
of the manufacturing processes of drug products
purporting to be sterile. In order to evaluate the propriety
of sterility assurance of the drug products, the whole
aseptic processing have to undergo process validation.
Process simulation is one of the validation methods to
evaluate not only the lling process but also the whole
aseptic manufacturing processing, using media or other
microbiological growth materials instead of actual
products. Included as a scope are manufacturing
process of sterile API and/or sterile in-process products
and the overall manufacturing processes of drug
products purporting to be sterile.
The operating personnel, operating environment,
and processing operation should also reect the actual
manufacturing process, including worst-case conditions.
The necessary information for conducting the tests
should be referred to the guideline that incorporates the
General Information of JP XV as the basic concept.
The number of units lled during a process
simulation test should consider the duration of runs; it
is generally recommended to determine based on the
batch size, preferably the size of 5000 units (g, vials,
etc.) or larger.
In consideration of process simulation testing, it is
recommended that the whole aseptic processing be
simulated, for there may be a risk of contamination in
the processes other than lling. Therefore, when a process
simulation test is conducted, it should be so planned that
all contamination factors assumed in normal operations
are included based on the identication of potential
contamination factors. The guideline with the basic
concept of the General Information of JP XV recommends
to conduct process simulation tests considering the
following ve points: (i) all permitted interventions and
events should be simulated based on the chart identifying
both permitted and non-permitted interventions and
events that may happen during the aseptic processing;
(ii) the duration of the process simulation run should be
adequate so as to include most of the manipulations
normally performed in actual processing; (iii)
process simulation tests should be conducted with the
permitted interventions and events normally performed
in actual processing conditions that include the longest

Table 8 Examples of Alert and Action Limits of Microbiological Monitoring

Target Grade Sampling point Action limits
Airborne particles A Air Less than 1 (CFU/m3)
B Air 10 (CFU/m3) or less
C Air 100 (CFU/m3) or less
Surface microorganisms A Equipment Less than 1 (CFU/plate)
Wall 1 (CFU/plate) or less
Floor 5 (CFU/plate) or less
B Wall 5 (CFU/plate) or less
Floor 10 (CFU/plate) or less
C Floor 30 (CFU/plate) or less
Microorganisms on hands/ngers A Hands/ngers Less than 1 (CFU/5 ngers)
B Hands/ngers 5 (CFU/5 ngers) or less
C Hands/ngers As appropriate
Surface microorganisms on personnel A Sampling at both arms, breast, head, Less than 5 (CFU/plate)
garments and shoulders
B Sampling at both arms, breast, head, 20 (CFU/plate) or less
and shoulders
C Sampling at both arms, breast, head, As appropriate
and shoulders
Alert limits should be determined in the level of meanC2s (s, standard deviation) based on the performance qualication and trend analysis of past data.
692 X: GENERAL TOPICS
and worst-case conditions. (e.g., maintenance of line
stoppages, repair and/or replacement of equipment
used in aseptic processing, replacement of lters in the
line, the number of personnel involved); (iv) the duration
of the simulation of the actual processing operations
should consider possible events that may occur during
the longest operation hours; and (v) consideration
should be given to intermission of the line by any activities
associated with normal aseptic processing operations.
The acceptance criteria of process simulation basi-
cally employ no positive result. However, when the
result of 5000 units/run in three consecutive runs is 0.05
or less, and the sum of the positive results in the three
consecutive runs is three or less, it can still be considered
complying provided that the source of contamination is
investigated and eliminated in a controlled manner.
During initial validation when a process is newly
established, it should be conrmed that the results of
three consecutive runs comply with the criteria. In
periodical validation (two per year as a principle except
for the line for multiple use with partially different
processing, in which case a process simulation run for
each product should be required), the result of one
process simulation run is employed. A positive result of
the periodical validation however should call for inves-
tigation and revalidation of the process.
Terminal Sterilization
The chapter Sterility Assurance of Terminally Sterilized
Drug Products in the General Information of JP XV
describes the recommendations regarding terminal ster-
ilization, of which contents have been referred to ISO
standards and USP requirements. It states as the basic
concept that the drug products to which terminal ster-
ilization can be applied should generally undergo the
sterilization condition such that a SAL of not more than
10K6 can be obtained. The SAL of not more than 10K6
should be judged by validation of sterilization process
using physical and microbial methods, but not by sterility
testing of sterilized products. Included as general require-
ments are the validation requirement of sterilization
process, microbial control program, sterilization
indicators, change control, etc. Important control factors
which may affect the selected sterilization method are
provided as recommendation. Steam sterilization method
will be explained in a separate section; in radiation
method for instance, important control factors as rec-
ommended are exposure time, absorbed dose and load
conguration for gamma rays, and electron beam charac-
teristics, exposure time, absorbed dose, and load
conguration of products for electron beam and X-rays.
The terminal sterilization cited in the General Infor-
mation of JP XV includes steam sterilization method and
dry-heat method as heat methods, EO method as gas
method, and radiation method and microwave method
as irradiation methods, among which the steam steriliza-
tion method of the heat methods is most widely employed
as terminal sterilization of drug products in Japan. The
reason mostly lies upon its capability of maintaining
stability of API. Besides, in terms of safety assurance of
drug product, the gas method and irradiation method
both pose possibility of complex degradation products
other than heat decomposition that will likely call for
enormous amount of testing for identication of the
degradation products as well as justication of safety
qualication; it thus has not been popular among pharma-
ceutical development companies.
It is recommended that the propriety of sterilization
by terminal sterilization methods should be judged by
employing an appropriate sterilization process control
and using a sterilization indicator suitable for the selected
sterilization method. In dry-heat method and/or gas
method for instance, Bacillus subtilis (strain name:
ATCC9372, IFO1372) is recommended as a sterilization
indicator.
While the basic concept of terminal sterilization
is provided in the General Information of JP XV, more
detailed and specic explanation of the practice has been
asked for operation; to this end, Manual of Manufac-
turing Sterile Drug Products by Terminal Sterilization
(guideline) incorporating, as the basic concept, the
General Information of JP XV and international harmoni-
zation, has been published in April 2007, with a
collaboration of a study group of MHLW Health Sciences
Study. The guideline of terminal sterilization will mainly
focuses on steam sterilization method of heat methods
but includes some items regarding other terminal ster-
ilization methods such as irradiation method as well.
Steam Sterilization
Steam sterilization is a sterilization method to kill micro-
organisms by steam under pressure. While a majority of
Japanese pharmaceutical industry employs the saturated
steam sterilization method whereby the subject to be
sterilized will be directly exposed to saturated steam,
there is also a sterilization method with unsaturated
steam in which the uid in the direct container will be
given moist heat energy from outside. In steam steriliza-
tion, a sterilization chamber is saturated with steam at
appropriate temperature and pressure and heated for
predetermined amount of time so as to kill the micro-
organisms. Important control factors which may affect
sterilization are thermal history (generally indicated as
F0), temperature, steam pressure, exposure time, load
conguration/density, and other necessary factors
dependent on the product, all required in routine ster-
ilization process control. Therefore, the temperature,
steam pressure and exposure time are to be monitored
continuously, and they should be included in the speci-
cations of the sterilizer.
Use of BIs
Sterilization indicators are used to control sterilization
process or as indicators of sterilization process; in steam
sterilization, use of a BI is recommended as a sterilization
indicator. BI, in other words, is used to indicate the
propriety of the steam sterilization method concerned.
A BI is prepared from specic microorganisms
resistant to the specied sterilization process and is
used to determine the condition and control of the
sterilization process. There are dry type BI and wet type
BI; the dry type BI is classied into two kinds. In one, lter
paper, glass or plastic are used as a carrier to which
bacterial spores are added, dried and packaged. In the
other, bacterial spores are added to the products or
similar products and dried. Packaging materials of BI

should show good steam penetration in steam steriliza-
tions. It should be conrmed that any carrier does not
affect the D-value of the spores. In the case of a liquid
product, it is also acceptable to use the wet type BI, spores
of which are suspended in the same solution as the
product or in a solution showing an equivalent effect in
the sterilization. However, when the spores of the specic
microorganisms are suspended in liquid, it is necessary to
ensure that the resistance characteristics of the spores are
not affected due to germination.
In the General Information of JP XV, Bacillus stear-
othermophilius (strain name: ATCC7953, IFO1737,
JCM9488, ATCC12980, IFO12550, JCM2501) is a typical
example of the specic microorganism recommended for
verication and control of the steam sterilization method.
In addition to this microorganism, other microorganisms
with the greatest resistance to the steam sterilization
procedure, found in the bioburden, can be used as the
BI. D-value of BI needs to be controlled in that the D-value
is generally determined by the survival curve method and
the fraction negative method. Marketed BIs with rec-
ommended microorganisms are often used in Japan; in
such cases, it is usually unnecessary to determine the
D-value before use provided the D-value indicated on
the label that has been determined by a standardized BI
evaluation resistometer under strictly prescribed con-
ditions is in accordance to ISO standard (ISO 111381).
As for a setting up procedure of BIs, a dry type BI is
placed at the spot least affected by the sterilization
procedure in the product or a suitable and similar
product showing an equivalent effect in sterilization. In
case of a wet type BI, spores of the BI are suspended in the
same solution as the product or in an appropriate similar
solution, and placed at the spot least affected by the
sterilization procedure.
Soybean casein digest medium is generally used
as culture for BI. General culture conditions are 558C to
608C for seven days in the case of B. stearothermophilius.
Steam Quality
Steam used in the steam sterilization should have the
quality (specied based on the quality of occulated
water) which has been predetermined and maintained
by the manufacture. It is thus often the case that the
manufacturer also predetermines the quality of the
source water for steam generation. The quality of steam
generally requires not containing impurities that may
deteriorate sterilization process, cause damages to ster-
ilization equipment and/or affect the subject to be
sterilized. The factors which need criteria for occulated
and source water of steam generation include eva-
poration residue, silica, iron, chlorine, phosphorus,
cadmium, lead, other heavy metals, conductivity, pH
and appearance, all of which are employed in ISO 13683
and EN285. There are also recommended criteria in that
the steam should contain non-condensable gas not more
than 3.5% in volumetric ratio and degree of dryness 0.95%
or more. It is also recommended that the uctuation range
of steam pressure before the decompression valve of
sterilizer should be within 10% and the decompression
ratio should be 2:1 or less.
In order to assure the quality of steam for the
steam sterilization procedure as well as to maintain the
54: JAPANESE REGULATORY REQUIREMENTS 693
quality of the source water for steam generation, water
of high purity such as UF water is generally used for the
source water for steam generation in Japan.
Overkill vs. Bioburden Cycle
As for determination of sterilization conditions using
microorganisms as indicators, there are overkill method,
half-cycle method, combination of bioburden and BI, and
absolute bioburden method, among which the overkill
method and half-cycle method are popular in Japan. One
of the reasons for such preference is that the overkill
method and half-cycle method are easy in control and
operation necessary for fullling the requirements
explained hereafter. For those drug products not appli-
cable for the overkill method and/or half-cycle method,
aseptic processing is generally employed in Japan.
According to the General Information of JP XV, in
the overkill method, it is assumed to conduct steriliza-
tion under the condition giving a SAL of not more than
10K6 regardless of bioburden count in the subject being
sterilized or the resistance of the objective microorgan-
isms to the sterilization. It is generally so dened that the
method employs a BI with known count of rec-
ommended microorganism of 1.0 or more D-value and
the sterilization condition providing 12D reduction or
equivalent of the BI. The half-cycle method is dened as
the one that, regardless of bioburden count in the subject
being sterilized or the resistance of the objective micro-
organisms to the sterilization, employs a sterilization
time of twice as long as that required to kill all of 106
counts of recommended organisms in the BI.
Absolute bioburden method is also dened in the
General Information of JP XV that the sterilization con-
ditions are determined by employing the D-value of the
most resistant microorganism found in the subject to be
sterilized or environment by the resistant estimation to
the sterilization procedure, and being based on the
bioburden count in the subject to be sterilized. As the
bioburden count, a count of mean bioburden added three
times of its standard deviation obtained by extensive
bioburden estimation is generally employed. When the
procedure is used, it is required to make frequent
counting and resistance determination of detected micro-
organisms to the sterilization in daily bioburden control.
In the combination of bioburden and recommended BI, it
is so dened that a count of mean bioburden added three
times of its standard deviation obtained by extensive
bioburden estimation is considered as the maximum
bioburden count, and the sterilization time is calculated
with the BI based on an objective SAL. When this
procedure is used, it is required to make frequent
counting and resistance determination of detected micro-
organisms to the sterilization in daily bioburden control.
When the bioburden estimation found a more resistant
microorganism than the BI spore, the microorganism
should be used as the BI. In other words, bioburden
method requires daily microbiological control (microbial
count and strain) to understand the microbial variation,
and the initial validation that has assumed the variation
factors and periodic validation are also required along
with occasional revalidation in the incidence of
694 X: GENERAL TOPICS
unpredictable variation, which altogether increase the
workload eventually.
In determination of comparative merits and
demerits of the overkill or half-cycle methods and the
bioburden method, it may be indicated there are very few
cases, with the manufacturing process under the current
Japanese GMP regulation, that products are being manu-
factured in the environment of poor quality, and thus the
bioburden count should be adequately low. For that
indication, the discussion in Japan has been divided: in
one, the validation of sterilization process should be
established based on a strict bioburden control in that
the strains of the resistant microorganisms and bioburden
count are determined; and in the other, such strict control
is not necessary, for the conditions dened in the overkill
method and/or half-cycle method will be adequate
provided the environment is maintained under GMP. In
current situation in Japan, the decision depends on each
manufacturer; resulting in the overkill method and half-
cycle method to be generally employed.