Auditing (self inspection) Inspection (External)

"Is a two-way process in which "Is a one-way process in which

compliance is reviewed
compliance is reviewed,
And
Definition But
discussions on how
there is no discussion on how
improvements could be done
take place". improvements could be done".

This process is generally used This process is usually used in

Used in
in the internal processes. the regulatory context.
 Informal self-inspection. (Auditing)
Stage (1) Takes place on a daily basis by both operators and
managers.

Next
Formal self-inspection. (Auditing)
Takes place on a regular basis → specified requirement of
Stage (2) GMP.
It involves the use of the QA staff as internal auditors to
review the system for compliance.
Finally

Stage (3) The external inspection coming from a number of sources.

 I. Internal inspection

Definition: "It is self inspection program that include written procedure

detailing what is to be inspected and at what frequency".

The frequency of self-inspections: 3 – 6 months

Reasons for internal inspection:

1.Determine the level of compliance.

2.Provide a stimulus for improvement.
3.Recommend corrective action.
4.Determine measures necessary to improve
• Equipment, environment
• Personnel, training.
• Operations, actions, procedures
5.Monitor improvement.
The self-inspection team is made up of a mixture of people including:
 experts in GMP.
 people familiar with the area in question.
 people from the production, QC and engineering would bring
different perspectives to the inspection.
 involving operators in the process could be considered a good training.
 The team leader, usually but not always a manager or supervisor, should
be from a different department to take a more impartial viewpoint.

The leader should have :

 the authority and experience to organize and manage a team activity.
 the resources to produce a report at the end of the process

*The team members are encouraged to be objective in their evaluation.

 II. External inspection

Sources Reasons
1) Inspections by national For all companies related to both
regulatory authority. manufacturing and marketing
(Most common type ) authorizations.
2) Inspections by overseas If the company is going to export its
inspectors. products.
For the company in entering into a contract
3) Inspection by other
manufacturing relationship with other
companies
companies
 Inspections by regulatory authorities may have different forms
according to:
1. the purpose of inspection.
2. the time spent since the last inspection.
3. the inspection history of the company.

A. Routine inspections

B. Concise inspections

C. Follow-up inspection

D. Special inspections
1) Routine inspections

A full review of all aspects of GMP within a facility.

• It may be announced or unannounced depending on:
1.the history of the company 2.policy of the country 3.previous inspections

 It is applicable under the following conditions

1. A new facility is opened.
2. New product lines.
3. Modification to processes.
4. If the company has a history of non-compliance to GMP.
5. If an inspection has not been carried out within the past 3 to 5
years.
2) Concise inspections

 Examination of limited aspects of GMP within a facility.

 Also known as abbreviated inspections.

 It is applicable when the company has a good history of GMP

compliance through routine inspections in the past.

 A company would normally be warned in advance about

a concise inspection (announced).
3) Follow-up inspections

 Limited to specific GMP requirements that have not been

observed or have been inadequately implemented.

 It is applicable under the following conditions:

1. To monitor the response to corrective actions arising from
a previous inspection.
2. They could be carried out between 6 weeks - 6 months
after the original inspection has taken place.

 The company would not necessarily know in advance about

the follow-up inspection (unannounced).
4) Special inspections

 Focus on the specific product.

 It is applicable if there have been :

 complaints about a specific product.
 a product recall.
 adverse drug reaction.

 The company would not be warned in advance (unannounced).

 The powers that an inspectorate has to deal with unsatisfactory

situations are controlled by national legislation.

 These powers often include:

 Suspension of the marketing authorization.

 Delay in approval of licenses or marketing authorizations.

 Delay in the issue of a GMP certificate.

 Initiation of a product recall.

 Closure of a facility (only used in an extreme case where failure of

a system or process has been identified, which presents a
significant risk to the patient).
  Policing role:
 The main approach that will be taken by regulatory inspectors during external

inspection.

 The primary character of an inspector must be an observer of facts.

 It is a key responsibility to report factually on the standards being achieved within the
factory.

 Advising role:
 The main approach that will be taken by inspectors during self-inspection.

 There are many occasions when an inspector takes the role of an advisor and uses the
opportunity of the inspection to suggest ways of improving manufacture or control.
 Inspectors deal with many people within a company from members of the

board to the shop floor operators.

 Good inspectors are able to both give and receive information on all occasions

and to recognize where it is most appropriate to ask particular questions.

 In case of questions about investments and company policies  a

board member or senior manager would be able to answer.

 But in case of technical questions such as “how is this process

carried out”, the inspector will be more likely to talk to someone in
the production area, such as the supervisor or the operator.
  The more professional an approach both parties make to an inspection, the
more relaxed they will be and the more effective the whole process will be.

 The key to a professional approach is preparation.

Inspectors Inspectees

 The company that prepares well for

an inspection will be a company that
 Must have a full agenda prepared
comes across as a more professional
 Be aware of the key issues to be
one to the inspector.
reviewed.
 Check that any questions or
 Inspectees should ensure that their
requests are made clearly and
responses and explanations are fully
that they are understood.
understood.
I- Preparing for an inspection

II- Conducting the inspection

III- Inspection reports

 I- Preparing for an inspection

1. Define the purpose and scope of the inspection.

2. Decide whether the inspection will cover the entire facility or

just part of it  to decide:

 How much time will be required to carry it out.

 When the inspection will take place.

For example, if a company produces a range of dosage types such as liquids,

tablets and sterile products, it may be preferable to take one area at a time,

rather than covering everything in one go.

 II- Conducting the inspection
 During the preparation stage, make a draft programme for the inspection.

 Whilst every inspection will be different in the detail, there are some
standard items that can be included in all of them:
 All inspections should start with an opening meeting to ensure everyone
has been briefed on the purpose of the inspections and that the objectives
are understood.

 A request should have been made for any help that will be needed by the
inspectors.

 It is useful to have an orientation tour of the facility, particularly if it is the

first visit for the inspectors.

 Once the introductions have been completed, it is time to begin the main activity
of the inspection which is finding facts to assess compliance to GMP.
 III- Inspection reports
 The final output of an inspection is a written report on

the findings.

 For non-regulatory inspections, this will often include

recommendations for improvements in levels of compliance.

 For regulatory inspections, the non-conformance is

highlighted, but it is generally left to the company to respond
and say how they intend to overcome the problem.

 In all cases, there should be a timeframe for a required

response.
 The report is split into four parts:
1. General information about the company can be provided by the
company itself.

2. Description of the inspection lists all the parts of the factory

that have been inspected.

3. Observations, either negative or positive, including any major

changes that have taken place since the previous visit.

4. Inspectors' conclusions, including the corrective actions

required and recommendations on how to improve if
appropriate.
QUALITY CONTROL TESTS OF
DIFFERENT PHARMACEUTICAL
DOSAGE FORMS
 Different Dosage Forms
A- Solid Dosage Forms
I- Tablets
II- Capsules
III- Effervescent granules
IV- Suppositories
B. Semisolid Dosage Forms
Ointments, pastes, creams and gels
C. Liquid dosage forms
Suspensions, emulsions, solutions
D. Sterile Products
Parenteral and ophthalmic products
E. Aerosols
Inhalations and spray
 E) Aerosols dosage forms
 Pharmaceutical aerosols are pressurized dosage forms
containing one or more active ingredients which upon actuation
emit a fine dispersion of liquid or solid materials in a gaseous
medium.
 Aerosols are of two types:

a) Inhalations are drugs or solutions of drugs administered by

nasal or oral respiratory route for local action on the bronchi or
for systemic effects through absorption from the lungs.
b) Sprays are aqueous or oleaginous solutions in the form of
coarse droplets or as finely divided solids to be applied topically to
the nasal or pharyngeal tract or to the skin.
Flammability and Physicochemical
combustibility characteristics

Evaluation of
Aerosols

Performance Biological
1. Flame Extension
 Done by spraying the product for 4 seconds into a flame.
 The flame will be extended.
 The exact length of the extended flame is measured by a
ruler.

2-Flash point
 Determined by chilling the product to a temperature
of -25°F and transfer the product to the test
apparatus, then increase the temperature slowly.
 The temperature at which the vapor ignites is
taken as the flash point.
 3-Closed drum
It is used to indicate the hazard of spraying aerosol in an enclosed
space in presence of a flame.
 Procedure

 A 55 gallon drum with a hinged lid is used for this test.

 A paraffin candle is placed into the drum and ignited.

 The test aerosol is sprayed into the drum through an opening

until an explosion takes place or for a period of 60 seconds,
whichever occurs first.
 The results of this test are used to classify the aerosol product
and, according to such classification, certain precautions are
written on the label.
•Vapour pressure:
Can be measured simply with a pressure gauge. Excessive
variation in pressure indicates the presence of air in the head
space.
•Density:
Is determined by the use of a hydrometer or a pycnometer.
•Moisture content
Can be measured by Karl Fishcer method or gas
chromatography.

•Identification of the propellant:

by gas chromatography or infrared spectroscopy.
1. Aerosol valve discharge rate
 Discharging the contents for a given period of time using a
standard apparatus.

 By reweighing the container, the change in weight per time is

the discharge rate (gram/second or gram/minute).

 Example:
Initial weight = 100 gm.
after 10 minutes of discharge → weight = 80 gm.
discharge rate = (100 - 80) / 10 = 2 gm/minute
2. Spray pattern
 Spray pattern is based on spraying the
aerosol on a piece of paper coated with a
dye-talc mixture.

 The dye goes into solution and is absorbed

onto the paper This will give a record of the
spray (finger print) which can be used for
comparison purposes.
3. Dosage with metered valves
(this test is used to determine reproducibility of dosage each
time and the amount of medication actually received by
patient)

a. Assay technique: where one or two doses are dispensed into

a solvent and the solution is assayed to determine the drug
content.

b. Another method:
Dispensing several doses.
The container is then reweighed
The difference in weight is divided by the number of doses
dispensed to give the average dose.
4. Net contents
A full container is weighed and then all its contents
are dispensed & reweighed.

5. Foam stability
 Visual evaluation
 By the use of a rotational viscometer.
6.Particle size determination:
can be determined by:
I-Cascade impactor method in which
o A stream of particles is projected through
a series of nozzles onto glass slides at high
velocity.
o The large particles become impacted
first on the lower velocity stages.
o The smaller particles pass on and are
collected at later stages.

II-Light scattering method

 Therapeutic activity: The aerosol is administered

whether by inhalation or by topical application to the test

area in the usual manner, and the amount of drug

absorbed can be determined to indicate the therapeutic

activity.

 Toxicity: Toxicity testing should include both inhalation

and topical effects.