PREAUDIT CHECK LIST
A |
General Information about the
Company |
1 |
Company name |
2 |
Address of
Company |
3 |
Name of production plant to be
audited and address if different from no. 2 |
4 |
Telephone (Switchboard) and
Fax number where the audit takes place |
5 |
Name of the “audit representative”
of the company for the audit (contact person) |
6 |
E-mail address and telephone
number of the contact person |
7 |
Name of product(s) subject to the
audit |
8 |
Approximate size of the plant |
9 |
Approximate number of employees |
10 |
Is this a pure production site or
are there other Headquarters functions (e.g. Research) located at the site? |
11 |
Are there other companies located
on the same area as the company to be audited? |
12 |
If so, which companies are these
and what types of products are produced? |
13 |
-specify the type of products
manufactured at your site (raw materials, starting materials, intermediates,
API’s and drug product) |
14 |
Does your company have a web site
that provides an overview of activities? If so, please specify: |
15 |
Is there other information about
your company the auditors could use for their preparation? |
B |
Quality related
Information |
1 |
Is there a Quality Policy in
place? |
2 |
Is there a commitment of the
management to comply with cGMP ? |
3 |
Does the company/plant maintain a
Quality Management System? Is the company/plant certified according to a
Quality Management System standard (e.g. ISO 9001 or based on ICH Q10)? |
4 |
Please provide information on the
latest inspections by national or international Regulatory Authorities
(authority, date, outcome) |
5 |
Is your Quality Unit (QU)
independent from Production (please provide organograms if possible) |
6 |
Please provide the names of
persons authorised to release materials to be sold |
7 |
Does your company conduct regular
internal audits (self- Inspections)? |
8 |
Is there an Internal Audit
schedule available? |
9 |
Do you have a CEP for the
product(s) to be audited? If so, would you provide us with a copy for each
product? |
10 |
Do you have an EDMF? If so, could
you provide a copy of the Applicant’s Part? |
11 |
Do you have a Site Master File
(SMF EU nomenclature; old DMF Type 1 US nomenclature) that you could provide
? |
12 |
Are Product Quality Reviews
performed? If yes, can you please provide your latest Product Quality Review
for the product(s) to be audited? |
13 |
Can you provide us with an example
of a certificate of analysis? |
14 |
Are the laboratories used on site
or are contract laboratories used? |
15 |
Do you use contract manufacturers
for the product(s) to be audited? If so, which steps are concerned? |
16 |
Name and address of any contract
manufacturers |
17 |
Does your company have a procedure
for Supplier Qualification including contract manufacturers? If yes please
provide it or summarise it |
18 |
Do you have an audit plan for
contract manufacturers and suppliers? If yes please provide a schedule
of audits performed in last 12 months and audits planned in next 12 months or
longer. |
19 |
Did your company employ
consultants within the past 24 months? |
C |
Product related
Information |
1 |
Is the
material to be audited manufactured by chemical processing, by classical
fermentation or is it a biotechnological product? |
2 |
Would you please provide us with a
brief description of the route of manufacture? |
3 |
Are any
materials used of animal or human origin in Production-if yes, please provide
details and relevant certificates for example TSE/BSE status |
4 |
Are the
Materials stored at the facilities to be audited? |
5 |
Please
provide name and address if alternative storage facilities are used. |
6 |
Is the production of
the product(s) performed in dedicated or multi-purpose equipment? |
7 |
Is the equipment used for
commercial and clinical material? |
8 |
Is the material
to be audited regarded as highly sensitising, potent or toxic and if so can
you provide a Material Safety Data Sheet? |
99 |
Are computer
systems used to control cGMP operations? If yes state which ones |
10 |
Are
microbiological aspects / specifications relevant? |
11 |
Is all cGMP
related documentation readily available? |
D |
cGMP
related Information |
1 |
Do you have a
recall procedure in place? |
2 |
Do you have a
procedure for handling of complaints? |
3 |
Do you have a
Change Control System in place? |
4 |
Are critical
process steps defined and validated? |
5 |
Is a batch
record review conducted by the QU before product release? |
6 |
Are
procedures in place to handle all investigations? |
7 |
-is there a
documented management review system in place |
8 |
Do you have
an OOS procedure in place? |
9 |
Has the
impurity profile of the material been established? |
10 |
Please
justify your re-test or expiry dates |
11 |
Are the
employees regularly trained and is the training documented? |
12 |
If
applicable, are dedicated production areas for highly sensitising materials
(penicillins and/or cephalosporins) or High Potency materials available? |
E |
Please
provide any additional information your company feels the auditors should be
aware of before the audit: |
AUDIT CHECK LIST
1 |
Introduction |
1.3 |
Scope |
|
Has
the company designated the point at which the production of the API begins? Can a
rationale be provided for this decision? Has
the decision been discussed with the respective authority? Are
the quality critical steps identified? |
2 |
Quality Management |
2.1 |
Principles |
2.11 |
A Certified Quality Management System (e.g. ISO 9001)
is implemented? (if yes, see chapter 20) |
2.12 |
Is there a quality policy? How is it brought to the attention of the employees? Is there a Quality Manual or equivalent documentation
that describes in detail how the Quality System is implemented? How does Management review effectiveness of quality
system |
2.13 |
Is the Quality Unit (QA/QC) independent of production? |
2.14 |
Is there an authorized person(s) for the release of IM
and APIs? Who is the person(s)? |
2.16 |
Are all deviations documented and explained? Are critical deviations investigated in a timely
manner? Is there a written procedure for handling investigations
(6.53)? Average days for completion? |
2.17 |
How is it ensured that materials are not released or
used before completion of evaluation by the QU? If not done by QU: Is an appropriate system in place? |
2.18 |
How is management notified of serious GMP deficiencies,
quality related complaints and/or product defects? Average time needed for information? |
2.2 |
Responsibilities of the QU |
2.21 |
Are there procedures that ensure that QU reviews and
approves all quality related documents? |
2.22 |
Non-transferable
responsibilities of QU: release/rejection of APIs and IM (to be sold) establish system to release/reject materials and labels review of critical process steps batch records ensure critical deviations are investigated approving specifications and master instructions approving all quality related documents ensuring conduction of internal audits approving contract manufacturers approving changes with quality impact approving validation documents ensure complaints are resolved ensuring calibration system isfunctioning according to
procedure executed ensuring that stability data is generated and reviewed performing product quality reviews |
2.3 |
Responsibilities for Production Activities |
|
procedure for preparing, reviewing and approving
instructions reviewing batch production records ensure all deviations and investigations are handled cleaning of facilities calibrations performed validation documents generated evaluation of proposed changes ensure that facilities and equipment are qualified |
2.4 |
Internal Audits |
2.40 |
Are regular audits performed? Is there an audit schedule? Is the schedule followed? |
2.41 |
Are audit findings and corrective actions documented? Procedure to notify management of audit findings? Are corrective actions completed within agreed time
(are there significant delays?) |
2.5 |
Product Quality Review |
2.50 |
Are regular Product Quality Reviews conducted for all
products? Frequency (dedicated, campaign)? Content (at least): review of critical IPC and API test results review of all batches failed review of all critical deviations review of process changes and impact on quality review of changes to analytical methods review of results of ongoing stability programmes review of returns, complaints, recalls review of adequacy of corrective actions defined in
previous review |
2.51 |
Evaluation and assessment for need ofadditional corrective actions to address recurring
issues and/or need for process or
cleaning revalidation |
3 |
Personnel |
3.1 |
Personnel Qualifications |
3.10 |
Adequate number of personnel? Qualification of personnel sufficient at different
levels? |
3.11 |
Are responsibilities of all personnel engaged in
manufacture in APIs in writing available? Are responsibilities periodically reviewed to ensure
they are current? |
3.12 |
Is regular training conducted? Are records of training maintained? Is effectiveness of training evaluated? How? |
3.2 |
Personnel Hygiene |
3.21 |
Do personnel wear clean clothing suitable for activity? Additional protective apparel where necessary (e.g.
Final Product Packing Rooms)? |
3.22 |
How is it ensured that personnel have no direct contact
with IM and APIs? |
3.23 |
How is it ensured that no smoking, drinking, chewing
and storage of food takes place? |
3.24 |
How are personnel with infectious diseases or open
lesions identified? Is there a procedure in place that these persons have
no product contact? |
3.3 |
Consultants Are consultants used to advise on any GMP related
activities? Is there an assessment of consultant’seducation,
training and experience? |
4 |
Buildings and Facilities |
4.1 |
Design and Construction |
4.10 |
Can cleaning and maintenance be easily performed based
on design of equipment and layout of facility? Have production and warehouse
facilities been designed to prevent contamination or cross contamination? If not, how is contamination prevented? |
4.11 |
Is there adequate space for placement of equipment to
prevent mix-up or contamination? |
4.12 |
Outdoor equipment raises concerns for contamination? |
4.13 |
Does flow of materials and personnel raise concerns for
contamination? |
4.14 |
Defined areas or control systems in place for the
following activities: receipt, identification, sampling of incoming materials quarantine before release/reject Sampling of intermediates or API’s holding of rejected materials before further
disposition? Packaging and labeling operations? |
4.15 |
Washing facilities and toilets available for personnel? |
4.16 |
Laboratory areas separated from production? |
4.2 |
Utilities |
4.20 |
All utilities that could impact on product quality are
identified and qualified? Are the utilities monitored and actions taken when
alert limits are exceeded? |
4.21 |
Adequate ventilation, air filtration and exhaust
systems in place? Are these systems designed and operated to prevent
contamination? |
4.22 |
Control of re-circulated air sufficient to avoid
contamination? |
4.23 |
Permanently installed pipework appropriately identified? Is pipework maintained and located in such a way as to
prevent contamination? |
4.24 |
Are drains designed to prevent back-siphonage or
microbiological contamination in areas where product is exposed? |
4.3 |
Water |
4.30 |
Water demonstrated to be suitable for intended use? |
4.31 |
Is Process water meeting drinking water quality as a
minimum standard? Is additional water treatment system in place? Is qualityof all grades of process water monitored at
points of use for physical/chemical attributes, total microbial counts,
objectionable organisms? Are actions taken when limits are exceeded? |
4.32 |
Tighter specifications needed to ensure quality? What are the specifications? |
4.33 |
Validation of treatment of (higher) water treatment? |
4.34 |
If claims are made for sterile or parenteral use: Monitor microbial counts, objectionable microorganisms and endotoxins |
4.4 |
Containment |
4.40 |
For highly sensitizing materials are dedicated production areas (facilities, air systems, equipment) in use? |
4.41 |
Dedicated production area for high pharmacological
activity |
4.42 |
Are there measures to prevent cross-contamination from
personnel,materials etc. for example moving from one production area to
another? |
4.43 |
Production of highly toxic, non-pharmaceutical
products, for example pesticides excluded from pharmaceutical production
facilities? |
4.5 |
Lighting |
|
Adequate lighting for e.g. cleaning and maintenance |
4.6 |
Sewage and Refuse |
4.60 |
Sewage to be removed timely |
4.7 |
Sanitation and Maintenance |
4.70 |
Buildings to be kept properly maintained, repaired and
cleaned |
4.71 |
Written procedures for cleaning for equipment and facilities in place |
4.72 |
Procedures for pest control in place? |
5 |
Process Equipment |
5.1 |
Design and Construction |
5.10 |
Equipment suitably located, easy to clean and maintain? |
5.11 |
Equipment surfaces do not alter product quality |
5.12 |
Equipment only used within the qualified operation
range? |
5.13 |
Major equipment and permanently installed pipework
identified |
5.14 |
Lubricants not in contact with IM and APIs?Otherwise
food grade lubricantsused? |
5.15 |
Precautions (measures) taken where equipment is opened
to prevent contamination? For example addition of seeds or sampling |
5.16 |
Are current engineering drawings available for
equipment, installations and utility systems? |
5.2 |
Equipment Maintenance and Cleaning |
5.20 |
Preventive maintenance programme in place? Schedule followed? |
5.21 |
Written procedures for the cleaning of equipment in
place? Do the procedures give sufficient detail to enable
operators to clean each type of equipment in an effective and reproducible
manner? |
5.22 |
Are equipment and utensils, such as sampling devices
cleaned, stored and where appropriate sanitized or sterilized to prevent
contamination or carry-over of a material that would affect the quality of
the IM or API? |
5.23 |
Continuous production or dedicated production
facilities: is equipment/ facility cleaned at appropriate intervals to
prevent build-up or carry over of contaminants for example degradants or
objectionable levels of micro-organisms? Is the cleaning frequency justified and documented? |
5.24 |
Is equipment cleaned between production of different
products? |
5.25 |
For multi-purpose equipment is the Maximum Acceptable
Carry Over and other Acceptance criteria for residues justified and
determined? Are the cleaning procedures validated? |
5.26 |
Equipment identified as to its content and cleanliness
status? |
5.3 |
Calibration |
5.30 |
Instruments critical for IM and/or API quality are
calibrated? How is critical defined? Written procedure in place? Schedule followed? |
5.31 |
Calibration done with standards that are traceable to
certified standards? |
5.32 |
Records of calibration maintained? |
5.33 |
Calibration status of instruments known? How (label, electronic)? |
5.34 |
How is it ensured that instruments out of calibration
are not used? |
5.35 |
If instruments have been shown out of calibration,
aredeviation investigations performed
to determine if this fact has an influence on the release of the IM/API? |
5.4 |
Computerised Systems |
5.40 |
Are GMP related computer systems validated? |
5.41 |
IQ, OQ for Hard- and Software available to demonstrate
suitability of computer hardware/software to perform task? |
5.42 |
Retrospective validation for existing systems if not
validated at time of installation? |
5.43 |
What controls are in place to prevent unauthorized
access? What controls are in place to prevent changes to data? What controls are in place to prevent omissions in
data? Is there an audit trail / documents available where
changes to data are recorded, who made the change, when the change was made
and of the previous entry? |
5.44 |
Written procedures for the operation and maintenance of
computerized systems available? |
5.45 |
Is the manual entry of critical data checked by
additional means (second operator or system itself)? |
5.46 |
Are all quality related incidents and deviations
relating to computerized systemsinvestigated according to defined procedures
investigated? |
5.47 |
Changes to the computerized system are made according
to a defined procedure? |
5.48 |
How is data protected in cases of system breakdowns? Back-up system provided? Is Recovery from back-ups tested periodically? |
6. |
Documentation and Records |
6.1 |
Documentation System and Specifications |
6.10 |
Is there a written procedure in place describing preparation,
review, approval and distribution of all quality related documents? |
6.11 |
How is revision, superseding and withdrawal of
documents controlled? Is a revision history maintained? |
6.12 |
Procedure in place for retaining all appropriate documents? Retention period specified? |
6.13 |
Retention period for APIs with expiry date: 1 year
after expiry (min.) Retention period for APIs with retest date: 3 years
after complete distribution (min.) |
6.14 |
Are corrected entries in documents dated and signed? Original entry still readable? |
6.15 |
Are documents promptly retrievable (copies or
electronic means acceptable)? |
6.17 |
Are specifications for all materials, IM and APIs
established? |
6.18 |
Are electronic signatures authenticated and secure? |
6.2 |
Equipment Cleaning and Use Records |
6.20 |
Are there records for the major equipment used ,
cleaning and maintenance showing the following date time product and batch number of each batch person who performed cleaning person who performed maintenance |
6.3 |
Records of Raw Materials, IM, API Labeling and
Packaging Materials |
6.30 |
Records of each delivery should contain: name of manufacturer/supplier identity and quantity supplier control or identification number number allocated on receipt date of receipt acceptable condition of received goods assessed result of tests and conclusion derived from this trace of use review of labels and packaging materials showing
conformity with specifications final decision release or reject |
6.31 |
Are master labels maintained? |
6.4 |
Master Production Instructions |
6.40 |
Are Master Production Instructions for each IM/API prepared dated signed independently checked by QU |
6.41 |
Do Master Production Instructions contain the following: name of product including document reference code complete list of raw materials accurate statement of quantities needed or calculation
of quantity production location and major equipment to be used detailed production instructions including sequences,
ranges of parameters, sampling instructions, IPC, time limits, expected yield instructions for storage |
6.5 |
Batch Production Records |
6.50 |
Are Batch Production Records checked before issuance
for correct version? |
6.51 |
Are the records showing an unique batch number (not for
continuous production)? |
6.52 |
The batch record should contain the following: date(s) and times (if appropriate) identity of major equipment identification of materials used actual results sampling performed signatures of the person(s) performing the operation IPC / laboratory test results actual yield, if appropriate description of packaging and labels used deviation/investigation results of release testing |
6.6 |
Laboratory Control Records |
6.60 |
Laboratory records should contain the following: description of sample including name, batch number or
code, date when sample was taken, quantity reference to test method cross reference to preparation of reference standards,
reagents and/or standard solutions complete record of all raw data record of all calculations statement of test result if they comply with
specifications signature and date of person(s) performing the testing signature of second person demonstrating review for
accuracy, completeness |
6.61 |
Other records to be maintained: modification to test method calibration of laboratory instruments stability testing performed OOS investigations |
6.7 |
Batch Production Record Review |
6.70 |
Is a written procedure for the handling of batch (laboratory)
record review available? |
6.71 |
Are batch (laboratory) records of critical steps
reviewed by the QU? Are they reviewed before the release of the API? |
6.72 |
Are all deviations, investigations and OOS reviewed as
part of the batch record review? |
6.73 |
Is the QU releasing all IM that are shipped outside the
control of the company? |
7 |
Materials Management |
7.1 |
General Controls |
7.10 |
Are written procedures available for handling of
receipt, identification, quarantine, storage, sampling, testing, approval or
rejection of materials? |
7.11 |
System to evaluate suppliers of critical materials in
place? Evaluation must show that supplier can consistently
provide material meeting specifications (7.31) |
7.12 |
Materials purchased against agreed specifications? Purchased from an approved (by QU) supplier? |
7.13 |
If supplier is not the manufacturer, is the original
manufacturer known? |
7.14 |
Change of source/supplier handled according to Change
Control procedures (chap. 13)? |
7.2 |
Receipt and Quarantine |
7.20 |
Upon receipt materials visually examined for correct labeling container damage broken seals tampering or contamination Are materials held under quarantine until released for
use? How is this done? |
7.21 |
Incoming materials are released before mixed with
existing stocks? Are procedures in place to prevent discharging
materials wrongly? |
7.22 |
If deliveries are made in non-dedicated tankers which
assurance is provided to demonstrate no contamination (one or more of the
following): certificate of cleaning testing for trace impurities audit of the supplier |
7.24 |
Is each delivery of materials identified (code or batch
number)? Is there a system in place to identify the status of
each batch? |
7.3 |
Sampling and Testing of Incoming Production Materials |
7.30 |
Is at least one test conducted to verify the identity
of incoming materials? If suppliers Certificate of Analysis is used instead of
testing a system for evaluation must be in place. |
7.31 |
(see also 7.11) Are 3 full analyses conducted before reducing testing? Is a full analysis performed at appropriate intervals
and compared with the suppliers certificate of analysis? |
7.33 |
How is it demonstrated that samples taken from the
material are representative? Are sampling methods described with at least number of containers to be sampled which part of the container amount of sample to be taken |
7.34 |
Is sampling done at defined locations preventing
contamination? |
7.35 |
Are containers from which samples are takenidentified? |
7.4 |
Storage |
7.40 |
Is material stored in a manner to prevent degradation
and contamination? |
7.41 |
Are fiber drums, bags and boxes stored off the floor? Is stored material suitably spaced to permit cleaning
and inspection? |
7.42 |
Do materials met their respective storage conditions? Is the FIFO principle followed? |
7.43 |
In case materials is stored outdoors: do labels remain legible are the containers cleaned before opening is it described in a procedure |
7.44 |
How are rejected materials held under a quarantine
system? |
8 |
Production and In Process Controls |
8.1 |
Production Operations |
8.10 |
Are weighing and measuring devices of suitable accuracy
for their intended use? Are the devices periodically calibrated with certified references? |
8.11 |
Do containers with subdivided material contain the
following information: name of material code or control number weight, if applicable retest date, if applicable |
8.12 |
How are critical weighing, measuring or subdividing
operation witnessed? Is an equivalent control used? If so what? |
8.13 |
Are all other critical operations witnessed or
subjected to equivalent control? |
8.14 |
Are actual yields compared with expected yields at
designated steps in production? |
8.16 |
How is the processing status of major units of
equipment indicated? |
8.2 |
Time Limits |
8.20 |
Are all specified time limits of the operating
instructions met? |
8.21 |
How are storage conditions for IM held for further
processing determined? |
8.3 |
In-process Sampling and Controls |
8.30 |
Are IPC established to monitor the progress and control
the performance of the processing steps? |
8.32 |
Are critical IPC approved by the QU? |
8.33 |
How is the qualification (training) of the production
personnel documented, if they perform the IPC? |
8.34 |
Are sampling methods for IPC described in writing? |
8.35 |
Does in-process sampling not cause the contamination of
sample and/or product? |
8.4 |
Blending of Batches of IM or APIs |
8.41 |
Are OOS batches blended with other batches meeting the
specifications? Are all batches individually tested prior to blending?
And do they all meet specification? |
8.43 |
Is the blending process adequately documented and the
blended batch tested for conformance to specifications? |
8.44 |
Does the batch record of the blended batch allow
traceability back to the individual batches? |
8.45 |
Are blending operations validated if physical
attributes of the API resulting from this step are known to be critical? |
8.46 |
How is it demonstrated that the blended batch does not
affect stability? |
8.47 |
Is the expiry/retest date based on the oldest batch in
the blend? |
8.5 |
Contamination Control |
8.50 |
How is it ensured that carryovers (e.g.
degradants) into successive batches of
the same IM/API do not affect the impurity profile of the API? |
8.51 |
What measures are taken in production to prevent
contamination of IM/API? |
8.52 |
What specific precautions are taken to avoid contamination of the API after purification? |
9 |
Packaging and Identification Labelling of APIs and IM |
9.1 |
General |
9.10 |
Are written procedures available describing receipt identification quarantine sampling examination/testing release of packaging materials and labels ? |
9.11 |
Are specifications for all packaging materials and
labels established? Are suppliers of primary packaging materials in contact
with the product qualified? |
9.12 |
Are records of each delivery of packaging materials and
labels kept? |
9.2 |
Packaging Materials |
9.20 |
Can containers/packaging material used provide adequate
protection against deterioration or contamination during transportation? |
9.21 |
Are containers cleaned so that they are suitable for
their intended use? |
9.22 |
Are written procedures for cleaning in place for
re-used containers? Are all previous labels removed or defaced? |
9.3 |
Label Issuance and Control |
9.30 |
Is access to label storage area limited to authorized
personnel? |
9.31 |
Are procedures in place to reconcile the quantities of
labels issued and used? Are discrepancies investigated and approved by the QU? |
9.32 |
Are labels bearing batch numbersnot used being
destroyed? |
9.33 |
Are all out-dated and obsolete labels destroyed? |
9.34 |
Are printing devices checked that the imprint conforms
to the print specified in batch record? Is an examination done to check if the correct label is
on the packed IM/API? (9.45) |
9.36 |
Is a representative label included in the batch record? |
9.4 |
Packaging and Labelling Operations |
9.40 |
Are written procedures in place ensuring that correct
packaging materials and labels are used? |
9.41 |
Is physical or spatial separation of labels done when
multiple labeling operations are done at the same time? |
9.42 |
Labels should indicate the following information (at
least): name of product identifying code and batch number storage conditions, when such information is critical
to assure quality |
9.43 |
If the IM/API is transferred outside of the control of
the manufacturer the label as well as requirements of 9.42 contain: name and address of manufacturer quantity special transport conditions, if applicable special storage conditions, if applicable (10.22) legal requirements, if applicable For APIs with expiry date: date to be included on label
and certificate of analysis For APIs with retest date: date to be included on label
and/or certificate of analysis |
9.44 |
Are packaging and labeling facilities inspected before
use to ensure that all materials not needed are removed? Is this inspection documented? |
9.46 |
Are sealsand other security measures used that will
alert the recipient that the material may have been altered?Please specify. |
10 |
Storage and Distribution |
10.10 |
Are facilities for the storage of materials available
supporting the claimed storage conditions (e,g, temperature, humidity)? Are records of the storage conditions kept? |
10.11 |
Are separate storage areas provided for quarantined,
rejected, returned or recalled products? Or is an alternative system used? If so, how is it
designed and qualified? |
10.2 |
Distribution Procedures |
10.20 |
How is it ensured that APIs/IM are not distributed
outside of the company before the
release of the QU? |
10.21 |
How are transportation conditions ensured so that the
quality of the product will not be adversely
affected? |
10.23 |
How does the manufacturer ensure that the transporter
knows and follows the appropriate transport and storage conditions? |
10.24 |
Are there systems in place to easily permit a
recall?Has its effectiveness been demonstrated? |
11 |
Laboratory Controls |
11.1 |
General Controls |
11.10 |
Are adequate laboratory facilities available? |
11.12 |
Are all sampling plans and testing procedures reviewed
and approved by the QU? |
11.13 |
Do the specifications set for the APIs include a
control of the impurities? If the API has a specification for microbiological
purity and/or endotoxins what appropriate action limits have been
established? |
11.15 |
Are all OOS results investigated? Is resampling after OOS described in a procedure? |
11.16 |
Are written procedures in place for preparation of
reagents and standard solutions? |
11.17 |
Are primary reference standards stored under
appropriate conditions? Is the source of the primary standard documented? |
11.18 |
If the primary standard is not obtained from an
officially recognized source, is appropriate testing conducted to fully
establish the identity and purity of the primary standard? |
11.19 |
Are procedures in place to prepare, identify, test
store and approve secondary reference standards? Is the suitability of the secondary standard determined
prior to use by comparing it against the primary standard? Are secondary reference standards periodically
re-qualified? |
11.2 |
Testing of Intermediates and APIs |
11.21 |
Is there an impurity profile established for every API? |
11.22 |
Is the impurity profile compared at appropriate
intervals against the impurity profile in the regulatory submission or
against historical data? |
11.3 |
Validation of Analytical Procedures |
|
See section 12.8 |
11.4 |
Certificates of Analysis |
11.40 |
Are authentic Certificates of Analysis issued for each
batch of IM/API? |
11.41 |
Information on the Certificate of Analysis: name of IM/API batch number and code number? date of release expiry date, if applicable retest date, if desired |
11.42 |
On the Certificate of Analysis, are all tests performed
listed, together with acceptance limits and numerical results obtained? |
11.43 |
Certificates of Analysis should be dated signed by authorized personnel of the QU show name, address and telephone number of manufacturer If Certificate of Analysis is issued by agents (chap.
18) the name, address and telephone number of the agents must be shown. |
11.44 |
If Certificate of Analysis is issued by agents the
name, address and telephone number of the laboratory that performed the tests
must be shown. It also should contain a reference to the original
manufacturer and to the original Certificate of Analysis. |
11.5 |
Stability Monitoring of APIs |
11.50 |
Is an on-going stability testing programme conducted? Do the results of the stability programme justify storage conditions
and expiry/retest dates (see also 11.61)? |
11.51 |
Are the test methods used in stability validated and
stability indicating? |
11.52 |
Are the stability samples stored in containers of the
same material as the market containers? |
11.53 |
Are the first three commercial production batches
placed on stability? |
11.54 |
Thereafter, is at least one batch per year added to the
stability monitoring programme? Are annually tests performed to confirm stability? |
11.55 |
For APIs with less than 1 year stability: Is testing performed monthly for the first three months
and at three month intervals after that? |
11.6 |
Expiry and Retest Dating |
11.60 |
Is an expiry/retest date assigned when the APIs are
transferred outside of the control of the company? |
11.7 |
Reserve/Retention
Samples |
11.71 |
Are reserve samples stored for 1 year after expiry date
or 3 years after distribution (whatever is longer)? For APIs are reserve samples stored for at least 3
years after complete distribution? |
11.72 |
Are reserve samples stored in same packaging system or
more protective than the marketed? Is the amount of sample sufficient to conduct at least
2 fullcompendial or internal
specification analyses? |
12 |
Validation |
12.1 |
Validation Policy |
12.10 |
Is the company's overall validation policy documented? (Could be combined with 2.12) |
12.11 |
Are all critical parameters defined during the
development (or from historical data)? Are the operating ranges defined? |
12.12 |
Are all critical operation steps validated? |
12.2 |
Validation Documentation |
12.20 |
Is a validation protocol established? Is it approved by the QU? |
12.21 |
Is the following specified in the validation protocol: critical process steps acceptance criteria type of validation number of process runs? |
12.22 |
Is a validation report prepared summarising the results
obtained, including recommendation of
changes to correct deficiencies? |
12.23 |
Are variations from the validation protocol documented
and justified? |
12.3 |
Qualification |
12.30 |
Is there policy or procedure for
Qualification/Validation?. Is Validation Master Plan available? Is appropriate qualification (DQ, IQ, OQ, PQ) conducted
for critical equipment and ancillary systems? Is operational qualification completed before Performance
Qualification / process validation activities? |
12.4 |
Approaches to Process Validation |
12.40 |
Is process validation (PV) conducted before commercial
distribution of API batches? |
12.42 |
Prospective Validation should normally be performed.
What is the justification of performing other types? Is the validation completed before commercial
distribution of the drug product? |
12.44 |
If retrospective validation is conducted for well
established processes, are the following requirements met: critical process parameters have been identified appropriate in-process criteria have been established no significant process failures have occurred impurity profiles have been established for the
existing API |
12.45 |
Are batches selected for retrospective validation
representative for all batches made during the review period? |
12.5 |
Process Validation Programme |
12.50 |
Are at least 3 consecutive successful production
batches made for prospective and concurrent validation? For retrospective validation are 10 to 30 consecutive
batches examined? If fewer batches are examined, what is the justification
for it? |
12.52 |
Has process validation confirmed that the process can
be reproducibly controlled within critical operating parameters and the impurity profile is within the specified
limits? |
12.6 |
Periodic Review of Validated Systems |
12.60 |
Are systems and processes periodically evaluated to
verify that they are still operating in a valid manner (e.g. through product
quality review)? |
12.7 |
Cleaning Validation |
12.70 |
Are cleaning procedures validated? If not, is there a justification? Is cleaning validation directed to situations where
contamination or carryover poses the greatest risk? |
12.71 |
If various APIs/IM are produced in the same equipment
and the same cleaning process is used, is a representative API/IM selected
for cleaning validation (on the basis of solubility, difficulty to clean and
calculation of residue limits based on potency, toxicity and stability)? |
12.72 |
Does the cleaning validation protocol include equipment to be cleaned procedures materials used acceptable cleaning levels parameters to be monitored analytical methods type of samples (swab, rinse) how samples are collected and labeled |
12.73 |
Does the type of sampling detect insoluble and soluble
residues? Is the sampling method capable to quantitatively
measure levels of remaining residues? |
12.74 |
Are the analytical methods sensitive enough to detect
residues or contaminates? How are residue limits established (on minimum known
pharmacological, toxicological or physiological activity or the most
deleterious component)? |
12.75 |
If claims on microbiological and/or endotoxin
specifications are made, does the cleaning validation take this into account? |
12.76 |
Are the cleaning procedures monitored at appropriate
intervals to ensure their effectiveness? |
12.8 |
Validation of Analytical Methods |
12.80 |
Are the analytical methods developed by the company
validated? How are Pharmacopoeial methods qualified? |
12.81 |
How is the degree of analytical validation (e.g. for
different steps of production) justified? |
12.82 |
Is the analytical equipment qualified? |
12.83 |
Are records of modified validated analytical methods
maintained? Is the reason for the modification documented? |
13 |
Change Control |
13.10 |
Is a formal change control system in place capable of evaluating all changes? |
13.11 |
Written procedures should be provided for the
identification, documentation, review and approval of changes. |
13.12 |
Are all changes impacting the quality of the API/IM
approved by the QU? |
13.13 |
Are changes classified (e.g. major, minor)? If not, how is the impact on the quality of the API
being evaluated? How is level of testing, validation, documentation
determined (scientific judgement)? |
13.14 |
How is it ensured that after a change all affected
documents are revised? |
13.15 |
Are the first batches evaluated after the change has
been implemented? |
13.16 |
If critical changes have been made, has the impact on
expiry/retest dates and process validation been evaluated? |
13.17 |
Are medicinal product manufacturers notified about
changes that could impact the API quality (especially physical attributes)? |
14 |
Rejection and Re-Use of Materials |
14.1 |
Rejection |
14.10 |
Are IM/APIs failing to meet specifications identified?
How? |
14.2 |
Reprocessing |
14.2.1 |
Are all steps where reprocessing is conducted part of
the filing documents? |
14.3 |
Reworking |
14.30 |
Is an investigation performed before a decision is
taken to rework a batch? |
14.31 |
Have reworked batches been subjected to appropriate evaluation stability testing to show equivalency to original process? Is concurrent validation performed if more than one
batch is affected? Is a report issued if only one batch is affected? |
14.32 |
Is the impurity profile of the reworked batch compared
with the one of the established process? If routine analytical methods are inadequate, are
additional methods used? |
14.4 |
Recovery of Materials and Solvents |
14.40 |
Do procedures exist for the recovery of materials? Do the recovered materials meet specifications for
their intended use? |
14.41 |
Do recovered solvents used in different processes meet
appropriate standards? |
14.42 |
Are recovered solvents been tested for suitability
before being combined with fresh or approved solvents? |
14.5 |
Returns |
14.50 |
Are returned APIs/IM identified and quarantined? |
14.51 |
Are returned materials evaluated on their quality before re-use? |
14.52 |
Are records of returned goods available containing name and address of the consignee API/IM, batch number and quantity Reason of return Use or disposal of API/IM |
15 |
Complaints and Recalls |
15.10 |
Is a written procedure available describing the
handling of complaints? |
15.11 |
Do the complaint records include the following: name and address of complaint name and phone number of person submitting the
complaint complaint nature (including name and batch number of
API) date complaint is received action taken (including person taking the action) any follow-up, if applicable response provided to the originator of complaint
including date of response final decision on API |
15.12 |
Are the records of complaints retained? For how long? Are trends or recurring complaints evaluated? |
15.13 |
Is there a recall procedure in place? |
15.14 |
Does the recall procedure specify who should be involved how the recall is initiated who should be informed how recalled material is treated |
16 |
Contract Manufacturers (including Laboratories) |
16.10 |
Is it ensured that all contract manufacturers engaged
comply with the GMP requirements of ICH Q7? |
16.11 |
How is the contract manufacturer evaluated for GMP
compliance? |
16.12 |
Is there a written contract (agreement) with the
contract manufacturer? Are the GMP responsibilities defined in detail? |
16.13 |
Does the contract permit to audit the contract
manufacturer? |
16.14 |
Is subcontracting by the contract manufacturer
excluded? If not, how is it ensured that the contract giver is
involved in prior evaluation of the subcontractor? |
16.15 |
Are all records kept at the contract manufacturer’s
site? How is it ensured that these are readily available? |
16.16 |
Does the contract manufacturer have a change control
system? How is it ensured that the contract giver is informed
about all intended changes of the contract manufacturer to the process? Does the contract giver approve all changes? |
17 |
Agents, Brokers, Traders, Distributors, Repackers, and
Relabellers (Agent) |
17.1 |
Applicability |
17.10 |
Is this not the original manufacturer of the API? (Then this section applies.) |
17.11 |
Does the Agent comply with the GMP requirements as
defined in ICH Q7? |
17.2 |
Traceability of Distributed APIs and IM |
17.20 |
Is the following information retained: identity of original manufacturer address of original manufacturer purchase orders transportation
documentation receipt
documents name or designation of API manufacturers batch number distribution records authentic certificate of analysis, including those of
the original manufacturer expiry/retest date |
17.3 |
Quality Management |
17.30 |
Has the Agent established a system of managing quality as defined in section 2? |
17.4 |
Repackaging, Relabeling and Holding of APIs and IM |
17.40 |
How does the Agent ensure that during repackaging,
relabeling and holding of APIs/IM no mix-ups and loss of identity and purity
of the API/IM occurs? Are these operations conducted under conditions
described in Q7? |
17.41 |
Is repackaging done under conditions to avoid
contamination? |
17.5 |
Stability |
17.50 |
Are stability studies conducted if the API is repacked
in a different type of container? |
17.6 |
Transfer of Documentation |
17.60 |
Does the Agent transfer all quality and regulatory
information from the original manufacturer to the customer? |
17.61 |
Does the agent provide the name of the original
manufacturer and the batch number to the customer? |
17.63 |
Is the specific guidance for Certificates of Analysis
described in section 11.4 followed? |
17.7 |
Handling of Complaints and Recalls |
17.70 |
Does the Agent maintain records of all complaints and
recalls that were brought to their attention? |
17.71 |
Does the Agent review the complaint together with the
original manufacturer for determining further action? |
17.72 |
Do the records of the Agents include responses from the
original manufacturer to a complaint? |
17.8 |
Handling of Returns |
17.80 |
Are returns to the Agent handled in the way described
in section 14,52? Is documentation maintained of returned APIs/IM? |
18 |
Specific Guidance for APIs Manufactured by Cell Culture
/ Fermentation |
18.1 |
General |
18.10 |
Are the GMP principles of the other sections complied
with? |
18.13 |
What measures are taken for Biotech processes to ensure
that raw materials (media, buffer components) are no source of
microbiological contamination? If applicable, is the bioburden, viral contamination
and/or endotoxins controlled at appropriate stages of production? |
18.14 |
Which controls are performed for steps prior to this
guide, e.g. cell banking? |
18.15 |
Which equipment and environmental controls are used to
minimize contamination? Are adequate acceptance criteria for quality and
frequency’s for monitoring set at the various steps of production? |
18.16 |
Are the following controls taken into account: maintenance of WCB proper inoculation and expansion of the culture control of critical operating parameters monitoring the process for cell growth, viability and
productivity harvesting and purification procedures monitoring of bioburden viral safety concerns (ICH Q5a) |
18.17 |
Is removal of media components, host cell proteins
process and product related impurities and contamination demonstrated? |
18.2 |
Cell Bank Maintenance and Record Keeping |
18.20 |
Is the access to the cell banks limited to authorized
personnel? |
18.21 |
Do the storage conditions of the cell banks ensure that
viability is maintained and contamination prevented? |
18.22 |
Are records of the use of vials from the cell banks and
storage conditions maintained? |
18.23 |
Are cell banks monitored periodically for suitability
for use? |
18.24 |
For handling of cell banks check ICH Q5a |
18.3 |
Cell Culture
/ Fermentation |
18.30 |
Are
closed and contained systems used when aseptic additions are needed? If
open vessels are used which measures and controls are used to minimise risk
of contamination? |
18.31 |
If use of open equipment can cause microbial
contamination which environmental controls are done? |
18.32 |
Are personnel handling the cultures appropriately
gowned? |
18.33 |
Are critical operating parameters including cell
growth, viability and productivity monitored? |
18.34 |
Is cell culture equipment cleaned after use? |
18.35 |
Is culture media sterilized before use? |
18.36 |
Are procedures
in place to detect contamination and to determine necessary action? Is the impact of the contamination evaluated? |
18.37 |
Are records of contamination maintained? |
18.38 |
Is multi-purpose equipment sufficiently tested to minimize
contamination? |
18.4 |
Harvesting, Isolation and Purification |
18.40 |
Are harvesting steps performed in equipment and areas
designed to minimize risk of contamination? |
18.41 |
Can the harvesting and purification procedures remove
or inactivate organisms in a way that the API is recovered with consistent
quality? |
18.42 |
Is all equipment cleaned properly after use? |
18.43 |
Is purification performed under controlled
environmental conditions if open systems are used? |
18.44 |
If equipment is used for multiple products additional
controls and testing is to be conducted. |
18.5 |
Viral Removal / Inactivation steps |
18.50 |
See ICH Q5a |
18.51 |
Are viral removal and inactivation steps performed
within their validated parameters? |
18.52 |
Are appropriate precautions being taken to prevent
viral contamination from pre-viral to post-viral removal/inactivation? Do open processing take place in areas that are
separate from other processing activities and have separate air handling
units? |
18.53 |
If equipment is used for different purification steps
is it appropriately cleaned? |
19 |
APIs for Use in Clinical Trials |
19.1 |
General |
19.11 |
Are the controls used consistent with the stage of
development? Are procedures flexible enough to provide changes as
knowledge of the process increases? If APIs are intended to be used for clinical trials, is
the API produced in suitable facilities with appropriate controls to ensure
the quality? |
19.2 |
Quality |
19.20 |
Is there an appropriate GMP concept in place? Is a procedure for approval of batches in place? |
19.21 |
Is there an independent QU in place? |
19.23 |
Are raw materials, packaging materials IM and APIs
tested? |
19.24 |
Are process and quality problems evaluated? |
19.25 |
Does the labeling of APIs for use in clinical trials
indicate the material as being for investigational use? |
19.3 |
Equipment and Facilities |
19.30 |
Is it ensured that during all phases of clinical
development the equipment is qualified, instruments calibrated, clean and
suitable for it intended use? |
19.31 |
Are materials handled in a way to minimize
contamination? |
19.4 |
Control of Raw Materials |
19.40 |
Are raw materials evaluated or tested? |
19.5 |
Production |
19.50 |
Is the production of APIs for use in clinical trials
documented appropriately according to the stage of production? Do these documents include information about materials
used, equipment, processing and scientific observations? |
19.6 |
Validation |
19.60 |
Is the equipment used qualified and the instruments
calibrated? (Validation is not expected!) |
19.61 |
If batches are produced for commercial use, then
section 12 is to be applied. |
19.7 |
Changes |
19.70 |
Are all changes adequately recorded? |
19.8 |
Laboratory Controls |
19.80 |
Are analytical methods used scientifically sound? (No
analytical validation required) |
19.81 |
Is a system to retain reserve samples in place? |
19.9 |
Documentation |
19.90 |
Is a system in place to document the information gained
during the development? |
19.91 |
Is the development of analytical methods appropriately
documented? |
19.92 |
Is it ensured that all information is retained for an
appropriate length of time? |
20 |
Quality Management System |
20.1 |
Quality Issues |
20.10 |
Has the organization established, documented,
implemented and maintained a quality management system in accordance with the
requirements of ISO 9000:2000? |
20.11 |
Is the effectiveness of the quality management system
continually improved? |
20.12 |
Does the organization manage these processes in
accordance with the requirements of ISO 9000:2000? |
20.13 |
Does the quality management system documentation
include: Documented statement of a quality policy and quality
objectives Quality
Manual Documented procedures required by ISO 9000:2000 Documents needed by the organization to ensure the
effective planning, operation and control of its processes Records required by ISO 9000:2000 |
20.14 |
Are documents required for the quality management
system controlled? |
20.15 |
Has a documented procedure been established identifying
the following controls needed: Approval of documents for adequacy prior to issue Review, update as necessary and re-approval of
documents Ensure that changes and the current revision status of
documents are identified Ensure that relevant versions of applicable documents
are available at points of use Ensure that documents remain legible and readily
identifiable Ensure that documents of external origin are identified
and their distribution controlled Preventing the unintended use of obsolete documents,
and to apply suitable identification to them if they are retained |
20.16 |
Have records been established and maintained to provide
evidence of conformity to requirements and of the effective operation of the
quality management system? |
20.17 |
Has a documented procedure been established to define
the following controls needed Identification Storage Retrieval Protection Retention time Disposition |
20.2 |
Management Responsibility |
20.20 |
Has
top management provided evidence of its commitment to the development and
implementation of the quality management system and for the continual
improvement of its effectiveness? |
20.21 |
Has
top management ensured that customer requirements are determined and met with
the aim of enhancing customer satisfaction? |
20.22 |
Has
top management established a quality policy? |
20.23 |
Has
top management ensured that quality objectives are established at relevant
functions and levels within the organization? |
20.24 |
Has
top management ensured that responsibilities, authorities are defined and
communicated within the organization? |
20.25 |
Has
top management appointed member(s) of management who have responsibility and
authority for quality management? |
20.26 |
Has
top management ensured that appropriate communication processes have been
established within the organization? |
20.27 |
Does
the top management review the quality management system, at planned
intervals, to ensure its continuing suitability, adequacy and effectiveness? |
20.28 |
Do the
outputs from the management review include the decisions and actions? |
20.3 |
Resource
Management |
20.30 |
Have
the resources for quality management been determined and provided? |
20.31 |
Is
competency for personnel who perform work affecting product quality based on
appropriate education, training, skills, and experience? |
20.32 |
Has
the organization determined the necessary competency for personnel performing
work affecting product quality? |
20.33 |
Does
the organization identify, provide, and maintain the facilities including:
Buildings, Workspace and associated utilities, Process Equipment, hardware
and software, Supporting services? |
20.34 |
Has
the environment needed to achieve conformity of product requirements been
determined and managed? |
20.4 |
Product
Realisation |
20.400 |
Is
planning of the organization’s product realization consistent with the
requirements of the other processes of the quality management system? |
20.401 |
Has
the organization determined requirements specified by the customer, including
the requirements for delivery and post-delivery activities? |
20.402 |
Prior
to the commitment to the customer (e.g. submission of tenders, acceptance of
contracts or orders or acceptance of change orders) are requirements
adequately reviewed? |
20.403 |
Has
the organization determined and implemented effective arrangements for
communicating with customers? |
20.404 |
Are
inputs relating to product requirements defined, documented and maintained as
a record? |
20.405 |
Are
outputs of the design and development provided in a form that enables
verification against the design and development inputs? |
20.406 |
Are
systematic reviews performed in accordance with planned arrangements at
suitable stages of the design and development? |
20.407 |
Is
design and development verification performed in accordance with planned
arrangements to ensure that the design outputs have met the design and
development input requirements? |
20.408 |
Is
design and development validation performed in accordance with planned
arrangements? |
20.409 |
Are
design and/or development changes identified and recorded? |
20.410 |
Are
the purchasing processes controlled to ensure purchased product (or service)
conforms to requirements? |
20.411 |
Does
purchasing information describe the product to be purchased? |
20.412 |
Have
the inspection or other activities necessary for ensuring that purchased
product meets specified purchase requirements been established and
implemented? |
20.413 |
Are
the production and service provision planned and carried out under controlled
conditions? |
20.414 |
Have
processes where deficiencies may become apparent only after the product is in
use or the service has been delivered been validated? |
20.415 |
Is the
product identified by suitable means throughout product realization?
|
20.416 |
Does
the organization exercise care with customer property while it is under the
organization’s control or being used by the organization? |
20.417 |
Is
conformity of product preserved during internal processing and delivery to
the intended destination? |
20.418 |
Has
the organization determined the monitoring and measurement to be undertaken
and the monitoring and measurement devices needed to provide evidence of
conformity of product to determined requirements? |
20.5 |
Measurement,
Analysis and Improvement |
20.50 |
Have
the monitoring, measurement , analysis and improvement processes been
planned, and implemented? |
20.51 |
Is
information relating to customer perception
monitored by the organization as to whether customer requirements have
been met? |
20.52 |
Are
internal audits conducted at planned intervals to determine whether the
quality management system: Conforms
to planned arrangements, requirements of ISO 9001 and the quality management
system Is
effectively implemented and maintained |
20.53 |
Are
suitable methods applied for monitoring and where applicable, measurement of
the quality management system processes necessary to meet customer
requirements?
|
20.54 |
Are
product characteristics monitored and measured to verify that product
requirements are met? |
20.55 |
Is
nonconforming product identified and controlled to prevent unintended use or
delivery? |
20.56 |
Is
appropriate data determined, collected and analysed to demonstrate the
suitability and effectiveness of the quality management system and to
evaluate where continual improvement of the effectiveness of the quality
management system can be made? |
20.57 |
Does
the organization continually improve the effectiveness of the quality
management system? |
20.58 |
Are
corrective actions taken to eliminate the cause of nonconformities and to
prevent recurrence? |
20.59 |
Has
the organization determined actions to eliminate the causes of potential
nonconformities in order to prevent occurrence? |
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