INSPECTION OF ACTIVE PHARMACEUTICAL INGREDIENTS

PHARMACEUTICAL INSPECTION CONVENTION
PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

PI 030-1
13 January 2009

AIDE-MEMOIRE

INSPECTION OF ACTIVE
PHARMACEUTICAL INGREDIENTS

© PIC/S January 2009
Reproduction prohibited for commercial purposes.

Reproduction for internal use is authorised,
provided that the source is acknowledged.

Editor: PIC/S Secretariat

e-mail: [email protected]
web site: http://www.picscheme.org

PI 030-1 1 of 24 13 January 2009

TABLE OF CONTENTS

Page

1. Document History .......................................................................................... 2
2. Introduction.................................................................................................... 2
3. Purpose ......................................................................................................... 2
4. Scope ............................................................................................................ 2
5. Aide-Memoire ................................................................................................ 4
6. Revision History........................................................................................... 23

1. DOCUMENT HISTORY

Adoption by Committee 12.11.2009
Entry into force of PI 030-1 01.03.2009

2. INTRODUCTION

2.1 The adoption of ICH Q7 as the first truly harmonised GMP guideline for active
pharmaceutical ingredients (APIs) and the associated development of
regulatory frameworks to implement the guideline as a regulatory standard
mark the beginning of a new era of regulation for medicines.

2.2 The adoption of ICH Q7 by PIC/S occurred in May 2001 with the current version
of the guideline having been available since 1 September 2007 as GMP
PE 009 (Part II).

2.3 The primary objective for implementing ICH Q7 is the reduction of the risks
associated with the manufacturing quality of APIs and this cannot be achieved
without an effective inspection system which addresses the specific aspects of
the global API industry.

3. PURPOSE

3.1 It is recognised that due to their background and experience the majority of
GMP inspectors are more familiar with the inspection of finished products.
Therefore, to assist inspectors not specialised in the inspection of API
manufacturers this document has been developed to provide training and
guidance for the preparation and performance of such inspections.

3.2 This Aide-Memoire should also contribute to a harmonised approach for
inspections of API manufacturers between the different PIC/S Members.

4. SCOPE

4.1 At the time of issue, this document reflected the current state of the art. It is not
intended to be a barrier to technical innovation or the pursuit of excellence.

PI 030-1 2 of 24 13 January 2009

4.2 This Aide-Memoire focuses on the preparation for inspections and chapters
and/or sections of GMP PE 009 (Part II) which are specific to the inspection of
API manufacturers or critical for the quality of APIs. For sections which include
requirements similar to those in GMP Guide Part I devoted to Finished Products
such as personnel, documentation, etc., please refer directly to GMP PE 009
(Part II).

___________

PI 030-1 3 of 24 13 January 2009

5. AIDE MEMOIRE

Inspection 1. Preparation of API inspection Supporting
Element documents
Workflow Inspection reports
Inspection
history Review the reports of any recent inspections carried out and Products Quality
the outcome Review(s) (PQR)
Basic If appropriate, contact the inspectorate that conducted the last
information inspection to verify the information
related to the Determine the number of different APIs produced at the site
APIs
Determine the classification of the APIs (antibiotics, hormones, Site Master File
Basic cytostatics etc.)
information
related to the Determine the intended use of the APIs (topic, oral, injectable,
site inhalation, etc.)

Basic For each API, establish;
information - grade (freeze dried, micronised, sterile, etc.);
related to - batch size; and
processes - number of batches produced per year

Determine if the facilities are multipurpose or dedicated

If APIs are potent or highly toxic determine the containment SMF
measures
Pharmacopoeia; CEP;
Review a list of manufacturing equipment ASMF (previously
DMF), CTD part 3.2;
Review a list of SOPs Batch Manufacturing
Record if appropriate
Review the flow of personnel and materials through finishing
areas Validation Master
Plan; list of activities
If manufacturing operations, products or services, are scheduled
outsourced establish the name and address of the
subcontractors

Review:
- API specifications and test methods;
- Process flow charts;
- Detailed description of the process;
- Stability studies results;
- Impurity profile;
- API starting materials definition etc.

If appropriate, contact assessors of the dossiers

Review validation status

Changes Review recent major changes (new product, equipment,
building renovation or extension etc.)

Review scheduled major changes

PI 030-1 4 of 24 13 January 2009

2. Quality Management System

Area of Notes Crucial questions/Show me Supporting
operations / documents
Approved and Are internal audits being performed 2.40
items documented schedule, as scheduled? Can they be
Internal audits which covers all GMP substituted by third party audits? 2.40, 3.30
(Self activities available How is the frequency of internal 2.41
inspections) audits determined?
Composition of the 2.41, 2.18
Product Quality team appropriate Is the composition of the audit team 2.50, 2.51
Review (PQR) determined according to an SOP?
Qualification of any Has consideration been given to:
external auditors
Effectiveness of the - Conflict of interest
system to plan the - Code of conduct
corrective and - Qualifications
preventive actions - Independence from the area

Verification of the being audited (e.g. Who
completion of an action inspects the QA function)
The flow of information
is effective How is the suitability of external
auditors assessed?
Regular PQRs
performed in a timely How does the company ensure that
manner (e.g. within corrective actions are effective and
three months from the are completed in a timely manner?
end of the period being
evaluated). How do they check the effectiveness
of preventive actions?
Data from in-process
controls, batch release How is the responsible management
analysis and other key informed about the results of the
quality indicators e audits?
included
Is the data evaluated for the
presence of trends, and are these
acted upon?

Are complaint, out-of-specification
(OOS) and deviation investigations,
reported, considered and evaluated
in the PQRs?

Are the PQR results used to re-
evaluate the expected monitoring
ranges in Batch Manufacturing
Records?

PI 030-1 5 of 24 13 January 2009

2. Quality Management System

Area of Notes Crucial questions/Show me Supporting
operations / documents

items A review of OOS, Are required changes highlighted in 2.5, 6.61, 6.72, 8.36,
critical IPC and API test the PQRs implemented through the 11.15
Complaints results, deviations, change control system?
complaints, returns and 2.5, 12.60
recalls, non How are complaints reported, 15.10
conformances and including orally, recorded and 15.11
related investigations, investigated?
including the 15.11
effectiveness of the Is the nature of the complaint 15.11
corrective and correctly reported – i.e. is it possible
preventive actions to establish if there is a recurring
conducted problem?

A review of changes Has the impact of this complaint on
conducted other batches been considered?

Stability program data Does the corrective action correctly
verified address the problem, or it is focused
on “customer satisfaction”? (i.e. the
Based upon the review, company looked for the root cause of
the validation status of the problem, or simply “reimbursed”
a manufacturing the originator of the complaint?)
process is evaluated Was source of the complaint
and recorded removed in an effective manner
through preventive actions?
All quality related
complaints recorded
and investigated
according to a written
procedure

Complaint records
include all relevant
details (date and
source of the
complaint, nature of the
complaint, references
to batch number and
production date)

The complaint
investigation report
identifies corrective
actions and follow
up/preventive actions

The final report
specifies the kind of
response provided to
the originator of the
complaint and the
decision on the status
of the product

PI 030-1 6 of 24 13 January 2009

2. Quality Management System

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Complaint records and Are complaints correctly evaluated in 13.12-13, 15.12
reports are evaluated in PQRs? (i.e. is there any evaluation of 15.13, 15.14
Recalls the PQRs in order to reoccurrence and trends?)
identify trends, product Are corrective/preventive actions 15.15
related frequencies, managed through the change control
and severity system?
Is the recall process clearly
The “recalls SOP” documented and easy to follow?
specifies the threshold
(by way of example Is there a requirement to inform the
cases, or other means) authorities, and request cooperation
for which a recall shall (in terms of advices and/or actions),
be considered in cases where the recall is related to
a potentially life-threatening
The “recalls SOP” situation?
specifies who can
initiate a recall, and
how the recall process
shall be managed. (i.e.
who is to be informed,
and how recalled goods
are to be treated and
stored)

The recall procedure
clearly defines how to
inform the regulatory
authorities in the case
of recall related to a
serious problem

Area of Notes 3. Personnel Supporting
operations / Cf. Scope 4.2 Crucial questions/Show me documents

items 3.

4. Building and facilities

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Product protection Have procedures been implemented 4.10
increases from early to protect the API from 4.10
General through to final contamination during the final
manufacturing steps stages of manufacture? (e.g.
sieving, milling and packaging)
The level of product
protection is dependent Have procedures been implemented
upon the product type to protect the API when exposed to
and the expected time each stage of the manufacturing
of exposure to the environment (sampling, loading,
environment unloading, etc.)?

PI 030-1 7 of 24 13 January 2009

4. Building and facilities

Area of Notes Crucial questions/Show me Supporting
operations / documents

items APIs with What are the additional controls? 4.10
microbiological SMF
APIs specific specifications require Have controls been implemented to 4.43
areas / additional controls ensure that the activities in
activities surrounding areas/neighbourhood 7.21, 7.22
Tank farms are not an actual source of
contamination? 4.10, 4.11
Solvent recovery plant 5.4
Washing rooms Have controls been implemented to
ensure that highly toxic non PIC/S Aide-Memoire on
Control rooms pharmaceutical materials Utilities (PI 009)
(herbicides, pesticides, etc.) are not 4.60
Compressed air / manufactured in the same 4.60
nitrogen / other utilities building/equipment as used for 4.21, 4.22
Sewage and refuse APIs.

HVAC Are the general condition of tanks
and ancillary equipment (pumps,
pipes, vents, etc.) appropriate for
their intended use?
Are all tanks and associated pipes
appropriately labelled and secure?

See recovery chapter

Are washing areas appropriately
managed and
controlled?(equipment flow, storage
of dirty and clean equipment,
labelling)

Have computerised systems been
validated?
Have the backup systems been
verified?
Are procedures in place for the
analysis of data?

Is waste effectively removed from
production areas (e.g. using closed
systems like containers or plastic
bags to prevent contamination of
other areas)?

Are all waste disposal systems
correctly identified?

Does the HVAC system provide an
appropriate environment for
finishing areas where APIs are
exposed?

PI 030-1 8 of 24 13 January 2009

4. Building and facilities

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Drinking (potable) Are records of CoA available? 4.30, 4.31, PIC/S Aide-
Water water acceptable if Has testing at an appropriate Memoire on Utilities (PI
suitable for intended frequency been conducted? 009)
Design use Does potable water meet at the WHO Guidelines for
minimum WHO guidelines (e.g. free drinking-water quality
Flow of Non-sterile API from chemicals such as
materials and intended to be used in carcinogens, toxic substances, 4.33
personnel a sterile drug metals, organochlorine pesticides,
Containment lindane, DDT, organic compounds, 4.34
Defined areas or other etc; radiologicals and micro- 4.14, SMF
control system for organisms)
different activities If water sourced from river, wells, 4.11
(storage, sampling, etc. and treated by the
quarantine, production, manufacturer, has the treatment 4.13
etc.) process been validated?
Potential contamination Have the affects of seasonal 4.22
and cross- variation and human activity on the
contamination has water quality been addressed? Is
been prevented by the the process monitored?
location and placement Is the water used in the final
of equipment isolation and purification steps
monitored and controlled for
Design of the microbial counts, objectionable
multipurpose use organisms and endotoxins?
containment area
Are the flow of materials and
personnel appropriate for the
processes?
Are appropriate indications
displayed in critical areas (gowning
instructions, labelling for
clean/unclean areas,
incoming/outcoming materials, etc.)
Has the containment area been
qualified for multipurpose use?

If HVAC is not dedicated, what
controls are in place to prevent
cross-contamination?

PI 030-1 9 of 24 13 January 2009

4. Building and facilities

Area of Notes Crucial questions/Show me Supporting
operations / documents

items

Penicillins and Are they produced in dedicated 4.40
cephalosporins areas? 4.41
Other highly 4.42
sensitizing, toxic, Are sensitizing, toxic and potent
potent materials materials either produced in 4.42
dedicated areas or are validated
Controls to prevent inactivation and/or cleaning
cross-contamination procedures established and
maintained.

Have procedures to prevent cross-
contamination been established?

Is the performance of these
procedures being monitored?

Are staffs exhibiting appropriate
behaviour and personal gowning
techniques to prevent cross
contamination?

Are measures in place to ensure
that cross-contamination from
equipment, materials and personnel
moving from one dedicated area to
another area is avoided?

5. Process equipment

Area of Notes Crucial questions/Show me Supporting
operations / documents

items 5.

This section is to be
developed at the next
revision of the Aide-
Memoire

Area of Notes 6. Documentation and records Supporting
operations / Cf. Scope 4.2 Crucial questions/Show me documents

items 6.

7. Materials management

Area of Notes Crucial questions/Show me Supporting
operations / documents
Critical materials and Have supplier control procedures
items their suppliers been defined and implemented? 7.11

Suppliers
qualification

PI 030-1 10 of 24 13 January 2009

7. Materials management

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Supplier evaluation Have the following been considered 7.31
in supplier control procedures?
Starting Approved suppliers list 7.12, 7.13
material from - a review of the history of supplier 7.20
animal origin Additional records National or international
with TSE risk - completion of a questionnaire by guidance documents
Changes are effectively the supplier including information (e.g. EP general
Change control managed through the about quality system, quality monograph 5.2.8)
Storage change control system certifications, third party audits, site
Transportation and master file etc… 7.14, 13.
storage for raw 7.20
materials, and - a supplier audit including QC labs 10.11, 5.40, 7.20
intermediates requiring (considered for critical materials)
special handling
Validated electronic - evaluation of samples (for new
systems for material suppliers)
status control are
acceptable. In such Does the list include the name and
cases, physical address of the manufacturer (not
segregation may not be only trader)?
required
Is it an updated and controlled
document?

Is it available for people in charge of
receiving goods?

- Origin of raw materials: country,
supply chain, veterinary inspection /
certificates, age of animals
- Type of tissue used, collection
method, risk of cross contamination
during the collection
- Manufacturing process: overview
of the process, reduction of the TSE
risk (validation), risk of cross
contamination, cleaning validation

- Traceability: supply chain,
availability of the information back to
the slaughterhouses / animals

Is the Change Control system used
to manage changes to materials
and suppliers?

What systems are in place to
ensure appropriate transport and
storage conditions have been
maintained?

Where status control of material is
by physical location are the
locations well marked?

Is access to these locations
restricted to designated personnel?

Where status control of material is
by electronic means, is access to
the electronic system restricted to
designated personnel?

PI 030-1 11 of 24 13 January 2009

7. Materials management

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Non dedicated tankers Does the cleaning procedure, and 7.22
Bulk materials certificate of cleaning, for non- 7.22, 8.51
Note: Section 7.22 is dedicated tankers cover accessory 7.33
Sampling applicable to reusable parts, including transfer hoses?
containers 7.34
Analysis Sampling plan If non dedicated reusable containers
are used, is there evidence that they 7.30
Sampling environments are properly cleaned? 7.31
appropriate for the
materials being Are sampling plans appropriate for
sampled each type of raw material being
selected for testing?
Identity testing
Extent and frequency Does each sampling plan include a
of testing rationale for the selected method?

Has consideration been given to the
sampling environment for each
material being sampled?

Does the plan take into account the
material type, its susceptibility to
microbial contamination, its use in a
particular manufacturing step and
the final dosage form?

Is each batch identity tested?

If reduced testing performed, how
was the supplier approved?

At what intervals is full testing
conducted?

PI 030-1 12 of 24 13 January 2009

8. Production and in process controls

Area of Notes Crucial questions/Show me Supporting
operations / documents

items All the production Are production operations actually 8.
General operations verified for performed in dedicated or PIC/S Aide-Memoire on
considerations compliance with the multipurpose facilities? the Inspection of
on the production documents Biotechnology
production specified in 6.2, 6.3, Are the critical parameters recorded manufactures (1.4)
operations and 6.4, 6.5 of the GMP and controlled?
on facilities Guide, and the process 1.1 § 4 Registered file
described in the ASMF Do formal procedures describing
Compliance to or module 3, part 3.2.1 the production process exist? 8.10, 6.52
registered file of CTD or as described
and general by ICH M4Q Do production operations
consistency correspond with the defined
Raw materials: process?
Production Dispensing area
Operations surfaces, equipment Is the facility monitored to ensure
and environment appropriate conditions are
maintained?
Critical weighing
activities independently Has the method of monitoring been
confirmed and verified verified?

Is an appropriate level of protection
given to centrifuges, filters, ovens,
etc?

Does the monitoring of the quality of
water demonstrate that the
specification has been met

Are the critical parameters trended?

Do the parameters stated in the
registered file relate to the
operations documented in the
Batch Record?

- Process parameters,

- IPC,

- Specifications for intermediates
and finished product

Does the facility have the capability
to manufacture the batch size of the
APIs produced?

Is the inspected site’s address
consistent with the registered file?

Are all production areas declared in
the registered file?

Are dispensing areas and
equipment fit for purpose?

Are containers suitable and 8.11
appropriately labelled? 8.12, 8.13
Is material status controlled?

Are all critical activities witnessed or
subject to equivalent controls?
Do production personnel verify that
materials are correct prior to use?

PI 030-1 13 of 24 13 January 2009

8. Production and in process controls

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Yield within expected Have appropriate yield ranges been 8.14
range set? 8.15
Time Limits Is the batch yield within range?
In-process Deviations documented For critical process steps, are 8.16
Sampling and and investigated deviations in yield investigated? 8.17, 14.2; 14.3
Controls 8.20, 8.21
Process status Are deviations documented and 8.30
indicated explained?
Reprocessing and Has an investigation been 8.31
Reworking performed for critical deviations 8.32
appropriately controlled and, if necessary, corrective actions 8.33
implemented?
Time limits for process 8.34
operations, and for the For each major unit of equipment is
storage of the processing status identified?
intermediates
Written Procedures What systems are in place to track
available for the materials for rework, or
monitoring and control reprocessing, and to prevent
of production process unauthorised use?

Acceptance Criteria Where time limits have been set,
appropriate to process are these being met?
step / stage Are deviations documented and
evaluated?
Critical in-process
controls are Do written procedures exist to
documented and monitor and control the production
approved by the Quality process?
Unit Are the procedures based upon
In-process controls development / historical
performed and information?
documented by
qualified staff Do the in-process controls and
acceptance criteria become more
Sampling Procedures stringent for the later processing
documented and steps?
scientifically sound
Has the Quality Unit given approval
for in-process controls?

Are qualified staffs performing in-
process controls?
Are adjustments made to processes
in accordance with pre-established
and validated limits?
Are IPC results documented in the
batch record?

Are there written sampling
procedures which are scientifically
sound?

PI 030-1 14 of 24 13 January 2009

8. Production and in process controls

Area of Notes Crucial questions/Show me Supporting
operations / documents
In process sampling : Are sampling procedures designed 8.35
items Prevention of to prevent contamination and
contamination and ensure the integrity of the sample? 8.40
Blending assurance of the
Batches of integrity of the sample Does the company blend batches
Intermediates and is this process defined and
or APIs Blending of batches controlled?
defined and controlled
Contamination
Control Only batches meeting Have all input batches been 8.40
approved specifications manufactured by the same process, 8.43
may be blended been individually tested and meet 8.44
specification? 8.45
Traceability of material
used in a blended batch Is the blended batch tested for 8.46
conformance with specification? 8.47
Validation of the 8.45, 8.50, 8.51, 8.52
homogeneity of the Is it possible to identify all the input
blended batch batches that make up the blended
batch?
Impact of blending
process on product Is the blending operation validated
stability to show homogeneity of the
combined batch where physical
Expiry / Retest date attributes of API’s are critical in the
determination dosage form?

Prevention of Does the blending operation
contamination of adversely affect product stability? If
batches by carry over so have further stability tests been
from a previous batch performed.

Is the expiry/retest date of the
blended batch based upon the
expiry/retest date of the oldest
batch in the blend?

Is the carryover of degradants and
microbial contamination, that could
impact upon the established API
impurity profile, prevented?

Consider:

- Frequency of inter batch
cleaning.

- Environmental controls

- Open processing
operations

9. Packaging and identification labelling of APIs and Intermediates

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Impact of packaging Do Packaging materials alter the 9.21
materials on product quality of the API or intermediate?
Packaging and quality
labelling

PI 030-1 15 of 24 13 January 2009

9. Packaging and identification labelling of APIs and Intermediates

Area of Notes Crucial questions/Show me Supporting
operations / documents

items

Representative label Does the BMR include a 9.36
representative label? 9.22
Prevention of cross
contamination if Are there appropriate procedures to 9.3
containers reused avoid mix-up and cross 9.43, 10.22
contamination?
The issue of labels must Consider: 9.46
be controlled
The labelling of an API - cleaning
must ensure traceability - removal of labels
and provided instruction
on any special transport Is there an effective system for the
or storage requirements issuing of labels?

Effectiveness of the If and API is transferred outside the
sealing system control of the manufacturer is the
name and address of the
manufacturer incorporated into the
label.
If required, are special storage
conditions incorporated into the
label.

Has the sealing system been
validated?

10. Storage and distribution

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Appropriate storage Is there adequate space including 4.11, 10.10
areas specific areas for returned, rejected, 10.10
Storage and quarantined materials? 7.42
distribution Controls of transfers 10.20
under quarantine Have the specified storage conditions
been fulfilled? 10.21
Transport methods and
conditions Are FEFO / FIFO rules met?

If quarantined material is to be
transferred, are there effective controls
and documentation in place to prevent
use before formal release by the
manufacturer?

Has the responsibility for the transport
been assigned?
Is the assignment appropriate?

How are the specified storage
conditions maintained during
transport?

PI 030-1 16 of 24 13 January 2009

10. Storage and distribution

Area of Notes Crucial questions/Show me Supporting
operations / documents
10.23
items
10.24
The traceability of Is the level of control over the
materials and products contractor for transportation
extends to the point of adequate?
first supply Consider:

- audits by the API
manufacturer

- agreements
- questionnaire, etc.

Is there a system in place for product
recall?

Area of Notes 11. Laboratory controls Supporting
operations / Crucial questions/Show me documents
See PIC/S Aide
items Memoire PI-023 11.

Area of Notes 12. Validation Supporting
operations / Crucial questions/Show me documents
Validation protocol 12.10, 12.11
items established and Is the company's validation policy 12.12
Validation approved by the Quality documented? 12.20
Policy Unit Are all critical manufacturing steps
Critical steps that validated? 12.21
Validation require validation and Is the validation protocol compliant
Documentation acceptance criteria with the company’s validation policy?
specified
Has the rationale for identifying
certain manufacturing steps and
operating parameters as critical, been
documented?

The validation What is the validation approach 12.10,
approach adopted adopted? 12.4
defined and Consider :
documented 12.22, 12.23
- prospective, concurrent, or
The results of validation retrospective
must be documented
Any identified - the number of process runs
deficiencies evaluated
and documented Are variations from the protocol
documented and justified?

PI 030-1 17 of 24 13 January 2009

Area of Notes 12. Validation Supporting
operations / Crucial questions/Show me documents
12.30
items Any corrective actions Have all qualification activities been 12.12, 12.40
Qualification implemented and completed before process validation 12.41
documented begins? 12.42, 12.50
Approach to
Process Qualification (DQ, IQ, If prospective validation has not been 12.43, 12.50
Validation OQ, PQ) conducted for performed, has the validation
critical equipment and approach taken been justified? 12.45, 12.50
Prospective ancillary systems (both
Validation new and existing), for Are batches released for commercial 12.52
intended process, as distribution, before completion of
Concurrent appropriate concurrent validation, subjected to a
Validation thorough monitoring and testing
All operations programme?
Retrospective determined critical to
Validation the quality and purity of Are batches selected for retrospective
the API are to be validation representative of all
Impurity Profile validated batches made during the review
period?
Prospective validation
consisting of at least
three consecutive
successful batches
must have been
completed before
commercial distribution
of the API

Where only a limited
number of API batches
are manufactured, or
where manufacture is
infrequent, concurrent
validation of at least
three consecutive
successful batches is
acceptable

The number of process
runs selected for
retrospective validation
should be sufficient to
demonstrate process
consistency. In general,
data from ten to thirty
consecutive batches
should be examined
Test results from
retained samples can
be tested to obtain data
for retrospective
validation

Process validation
should confirm that the
impurity profile of each

PI 030-1 18 of 24 13 January 2009

Area of Notes 12. Validation Supporting
operations / Crucial questions/Show me documents

items API is within the limits Are Product Quality Reviews used to 12.60, 2.5
specified confirm that the process under review
Periodic There should be a remains validated? 12.71
Review periodic review of 12.73
systems and processes Are cleaning procedure validated? If 12.76
Cleaning with respect to not, is there any justification? 12.74
validation validation status Is cleaning validation directed to 12.75, 5.21, 5.23
Focus: multi purpose situations that poses the greatest
facilities and final risk?
manufacturing steps
Are documents available regarding
Rational behind the use risk assessment which consider:
of either validated or -characteristics of contaminants (e.g.
non validated cleaning toxicity, solubility, potency and
methods for equipment stability)
used at different stages -equipment (product contact material
of production and relative surface area, places
difficult to clean)
Cleaning procedures -process flow (purification steps, bulk
are to be validated size, product change over)
-at the minimum, selection of
Sampling methods product(s) which represent(s) the
involving rinse/swab, worst case scenario (product change-
with an acceptable over, maximum acceptable residue
recovery, validated limit, etc.)
(including sampling for
microbiological Are the cleaning procedures routinely
assessment) used in production the same as those
Analytical test methods used in the validation studies?
appropriately validated Are the cleaning methods applied in
production the same methods as
Microbiological aspects those used in the validation studies?
Is cleaning routinely performed after
When processes and the manufacture of the same number
equipment including of batches?

Are personnel performing sampling
properly trained and assessed?
Is the sampling method used to
monitor cleaning procedures the
same method used in the validation
studies?

Is the analytical test method
sufficiently sensitive related to the
established residue limits?

Has inhibition of microbial growth by
residue been considered during test
method validation?

Has the effectiveness of
cleaning/sanitization procedures been

PI 030-1 19 of 24 13 January 2009

Area of Notes 12. Validation Supporting
operations / Crucial questions/Show me documents
water system have to
items be controlled for validated?
microbiological Are “clean/dirty status” hold times and
contamination, there sanitizer residue limits correctly
shall be appropriately considered?
validated Is the water used for cleaning/rinsing
cleaning/sanitization appropriate for the next
procedures manufacturing step?

Area of Notes 13. Change Control Supporting
operations / Cf. Scope 4.2 Crucial questions/Show me documents

items 13.

14. Rejection and re-use of materials

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Specifications Has a rationale for solvent / material 14.41, 14.42
Solvent and appropriate for the specification been documented? 14.41
material intended use 7.3, 16.
Recovery If it is to be used for multiple 14.40, 14.43
Outsourced services processes, does the specification 14.41, 14.43, 5.21
Rejection are to be controlled account for the presence of
contaminants introduced from other 14.1
Documents and records processes?
must be maintained
Is the level of control over the supplier
Identification and of outsourced services appropriate?
controls of equipment (see section 7.3);
used for recovery,
transportation and Are relevant SOPs, batch records and
storage of solvents CoA available?
Are recovered solvents formally
Rejected APIs and approved and released for use?
intermediate materials
shall be quarantined Is the identification of the equipment
and recorded used recorded or cross referenced in
The disposition of the batch record?
material shall be Are appropriate procedures in place
recorded to avoid mix-up and cross
contamination?

Do procedures exist and are they
adequate?
How are materials identified and
stored?
Is a list of rejected materials
maintained?
Do the Certificates of Destruction for
disposed materials correspond with
the list of rejected materials?

PI 030-1 20 of 24 13 January 2009

14. Rejection and re-use of materials

Area of Notes Crucial questions/Show me Supporting
operations / documents

items Is an investigation performed before a 14.30
Reworking decision to rework is carried out?

Returns The impurity profile of a Have reworked batches been 14.31
reworked batch shall be subjected to:
comparable to routine 14.32
production batches - appropriate evaluation 14.32
Additional testing and 14.50
test methods if routine - stability testing 14.51, 14.52
test methods are found - a review to show equivalency
to be inadequate
to original process?
Policy on returns Is validation performed if more than
documented one batch is affected?

Records of returns Is a report issued if only one batch is
maintained affected?

Are the impurity profiles of reworked
batches similar to routine production
batches?

Are routine analytical methods
adequate for the analysis of reworked
batches?

Will the methods detect additional
degradants or other impurities?

If the company accepts returns, are
the returned APIs and intermediates
identified as returns and subsequently
quarantined?

Does the procedure for handling
returned product require the reason
for returning the product to be
identified?

Do the company’s records allow
identification of the transportation and
storage history of the product, whilst
the product was outside the
company’s control?

Are the details recorded in the
documentation associated with the
returned product adequate and
appropriate?
Is returned product appropriately
dispositioned for reprocessing,
reworking, or destruction?

Area of Notes 15. Complaints and Recalls Supporting
operations / Cf. Scope 4.2 Crucial questions/Show me documents

items 15.

PI 030-1 21 of 24 13 January 2009

16. Contract manufacturers (including Laboratories)

Area of Notes Crucial questions/Show me Supporting
operations / documents

items 16.

Cf. Scope 4.2

17. Agents, Brokers, Traders, Distributors, Repackers and Relabellers

Area of Notes Crucial questions/Show me Supporting
operations / documents

items

General Relevant sections of 17.10, 17.11
Part II are applicable to
Agents, Brokers,
Traders and Distributors
(e.g. chapters 2, 3, 4, 6,
7.4, 9, 10, 11.4, 14.52,
15).

Repackers and 17.11, 17.40
relabellers are
considered as
manufacturers (full
compliance with Part II
required)

Traceability of Effectiveness of the For some APIs, consider the 17.20
APIs and system availability and completeness of
intermediates required documentation back to the
original manufacturer

Are these records readily available?

Transfer of Is the customer informed of any 17.60
information additional manufacturing operation
carried out on behalf of Agents,
Brokers, Traders, Distributors,
Repackers and Relabellers (e.g.
micronisation, Gamma irradiation,
freeze-drying)?

Are the original API manufacturer’s 9.43, 17.61
name, address and the batch
number(s) supplied provided to the
customer?

Is the original API manufacturer’s 11.44
name and address included on the
CoA and displayed on labels?

Is quality or regulatory related 17.60
information exchanged between
partners in a timely manner?

In case of quality related problems, 17.71, 17.72
are Agents, Brokers, Traders,
Distributors, Repackers and
Relabellers involved?

Are they informed of any investigation
and actions undertaken?

PI 030-1 22 of 24 13 January 2009

17. Agents, Brokers, Traders, Distributors, Repackers and Relabellers

Area of Notes Crucial questions/Show me Supporting
operations / documents

items

Repackaging Do procedures, records, and 17.4
relabelling environmental monitoring indicate that
controls are in place to avoid mix-up,
contamination and cross-
contamination?

Are samples retained? 11.7

Stability Is retest or expiry date available? 17.20
17.50
When an API is repacked in a
different type of container are the 17.50
mandatory stability studies 11.5
conducted?

If micronisation, Gamma irradiation,
freeze-drying is performed on behalf
of the Agents, Brokers, Traders,
Distributors, Repackers and
Relabellers are the mandatory
stability studies conducted according
to section 11.5?

18. APIs manufactured by Cell Culture / Fermentation

Area of Notes Crucial questions/Show me Supporting
operations / documents

items

See PIC/S Aide PIC/S Aide-Memoire
Memoire PI-024 on QC Laboratories

19. APIs for use in Clinical Trials

Area of Notes Crucial questions/Show me Supporting
operations / documents

items 19.

This section is to be
developed at the next
revision of the Aide-
Memoire

6. REVISION HISTORY

Date Version Reasons for revision
number

PI 030-1 23 of 24 13 January 2009

Acronyms:

ABTDRR: Agents, Brokers, Traders, Distributors, Repackers and Relabellers

APIs: Active Pharmaceutical Ingredients

ASMF: Active Substance Master File

BMR: Batch Manufacturing Record

CEP: Certificate of the European Pharmacopoeia

CoA: Certificate of Analysis

CTD: Common Technical Document

DMF: Drug Master File

OOS: Out of Specification

PQR: Product Quality Review

SMF: Site Master File

SOP: Standard Operating Procedures

Bibliography:

1) EMEA Note for Guidance on quality of water for pharmaceutical use
(http://www.emea.europa.eu/pdfs/human/qwp/015801en.pdf)

2) WHO Guidelines for drinking-water quality
(http://www.who.int/water_sanitation_health/dwq/guidelines/en/index.html)

3) Related PIC/S Aide Memoires and guidance documents:
- Quality Controls Laboratories (PI 023)
- Biotech (PI 024)
- Utilities (PI 009)
- Explanatory notes for industry on the preparation of a Site Master File (PE 008)

These documents are available on the PIC/S website: (http://www.picscheme.org)

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PI 030-1 24 of 24 13 January 2009