Drug product inspection & change control

 “ AN ACTIVITY OF MEASURING ,
EXAMINING , testing one or more
characteristics of a product and comparing the
results with specified requirements in order to
establish confirmity for each characteristic”.

• To enforce Good Manufacturing practices in
pharmaceutical manufacturing facilities.
• To authorize the manufacturing of specific
pharmaceutical product
• To monitor the quality of pharmaceutical products
in distribution channels from point of
manufacturing to delivery of recipient.

21 CFR PART 11
211.134 Drug product inspection.
(a) Packaged and labeled products shall be examined during
finishing operations to provide assurance that containers and
packages in the lot have the correct label.
(b) A representative sample of units shall be collected at the
completion of finishing operations and shall be visually examined for
correct labeling.
(c) Results of these examinations shall be recorded in the batch
production or control records.

• Evaluation of the establishment’s compliance with GMP requirements,
particularly regarding proper environment, quality management, personnel,
facilities and equipment.
• Evaluation of the procedures and controls implemented in the manufacture of
the product (pre-approval batches), to determine whether they are in
conformity with the application commitments.
• Audit of the completeness and accuracy of the manufacturing and testing of
information submitted with the application, and of the conformity of
preapproval batches with planned commercial batches (process validation
protocol).
• The collection of samples for the validation or verification of the analytical
methods included in the application.

• Pre approval inspections are specifically carried for new chemical entities , drugs
with narrow therapeutic range, New applicants or manufacturers.
• This involves an inspection team(analysts& other Specialists expertised) And
includes review of the application.
Carrying out
• Emphasis should be placed on manufacturing process including data verification.
• Collection of relevant manufacturers analytical documentation, a copy of
analytical methods used by inspected laboratory.
• Method validation report for reproducing analytical methods.
• Samples are tested in accordance with methods described in the application.

• They cover inspection of the production and control of final dosage forms of
pharmaceutical products.
• They are directed to government inspectors to assist them in assessing manufacturers’
compliance with GMP.
These guidelines also has relevance in other contexts
1. Self inspection / internal audit of a factory
2. Inspection by independent person / group as review of quality system of company in
compliance with BSI , ISO
3. Audit of manufacturer or supplier by authorized agents of customer.
Objectives:
1. Sequential examination of production &control activities on basis of GMP guidelines
issued by WHO.
2. Verification that production & quality control procedures employed in manufacturing
of specific products in accordance with data provided in licensing application.

PROCESS:
• Routine inspection- when non compliance with GMP, not inspected from 3-5years.
• Concise inspection-Manufacturers with a consistent record of compliance with GMP
through previous routine inspections are eligible for concise inspection.
• Follow up inspection (Reinspection)- To monitor the result of corrective actions.(6
weeks to 6 months from initial inspection).
• Special inspection- To undertake spot checks following complaints or recalls related to
suspected quality defects in products.
Frequency & duration of inspections
• For all companies inspection should be carried out regularly(annually)
• For large companies marketing wide range of products inspection may be split into
several visits over a longer period.
• The length of inspection depends on size of company & purpose of visit. It may also
depend on no of inspectors. It may extend from days to weeks.

Objectives
1. Protection of patients and members of the public from malpractice by distributors
and suppliers of drugs.
2. Adherence to the drug laws and regulations governing compounding, distribution,
importation, export and storage of drugs.
3. High ethical and professional standards of pharmaceutical practice.
• Carried out by drug inspectors. Inspectors should normally be pharmacists who
have working experience in community and/or hospital pharmacy. Where persons
other than pharmacists are employed as drug inspectors, they should be
adequately experienced in drug control affairs and suitably trained in inspectorate
functions.

The inspector will be expected to inspect
establishments such as:
(a) pharmaceutical manufacturers in respect of drug distribution,
(b) pharmaceutical importers/exporters,
(c) pharmaceutical wholesalers and retailers,
(d) hospital pharmacies/clinics,
(e) ports and international border posts,
(f) drug warehouses, stores and unauthorized markets.

Methods of Inspection
 Comprehensive/routine inspection. This form of inspection is
generally reserved for a new pharmaceutical establishment, when an
establishment is applying for permit to extend its scope of operations
beyond that for which it was originally licensed, has made important
changes in key personnel or is changing premises, has not been
inspected for a long time (3–5 years), or when there is information
(even of an informal nature) of serious lapses.
 • Concise inspection. This is reserved for establishments that have
previously been inspected with a view to assessing standards of good
pharmacy practice.

 Follow-up inspection. This is normally carried out to ensure that
corrective measures have been undertaken following advice and
notice given during a previous inspection.
 special inspection. This is undertaken to deal with specific
complaints received about lapses or non-compliance with
standards of professional practice. The inspection should
preferably be unannounced.
 Investigative inspection. This type of inspection is used to
assess the performance of a new establishment whose scope of
operation was previously unknown.

Frequency of inspection
Inspections should be held regularly. Premises should be inspected at least once
every 12–18 months. Where contravention is often noticed, the inspection should be
more frequent (e.g. every six months). For premises with a good record, less
frequent inspections may be needed.
References/information sources for inspector for inspection:
• Existing national and international drug laws and regulations covering aspects
like licensing, GMP, good distribution practice, good pharmacy practice,
promotion of pharmaceutical product, controlled drugs, counterfeit, spurious or
substandard pharmaceutical products.
• Codes of inspection (national and regional), where in existence.
• Codes of professional ethics.
• Health consequences of drug abuse and misuse.
• Available data on imports/exports/prohibited drugs.

• Quality control is the Process of verification or correction of Quality of
product when deviations are found to be more than the expected.
• Quality control system verifies and Maintains desired level of quality in
the existed product By careful planning , use of proper equipments and
continuous inspection and corrective action as required.

• The safety and efficacy of final product is largely dependent on the quality of the
bulk active drug substance.
• To reduce quality risks, the inputs can be inspected prior to production.
• Samples are randomly taken and checked.
• An experienced inspector inspects the products to ensure that
1. the raw materials meet the specified standards.
2. Whether the development team has clearly communicated with the
manufacturing team.
3. Whether the equipment for mass production is similar to that of the prototypes.

• Inspect the test results From in process tests performed for conformance
with established Sampling tests and protocols, Analytical methods and
specifications.
• The inspection confirm that in process tests were performed as per plans
and results are obtained within specified limits.
Example – weight variation test , hardness test etc.

Classification
Trial run inspection : tools and machines are checked before the operation.
First off inspection : the items produced in the first run are inspected and examined
With respect to specifications.
Inspection by self control : performed by operators, controlling operations at
various levels of operation
Decentralized inspection : semi finished goods are inspected either by machines or
by production line.
Centralized inspection : performed by well experienced operators and highly
sophisticated equipments. Hence this give more reliable results.

 Component dominant : incoming material should be inspected for
Required specifications.
 Set up dominant : an operation when set up at a level remains at that
level for long time. Hence a produced initially is found free from defects
and following specifications, Then the operation can be cleared for
continuous operation.
 Machine dominant : equipment drifts away after continuous operation,
hence they need to be inspected.
 Operator dominant : Quality also depend on operator skill.
 Information dominant : sop’s
 Record dominant : the written records and documentation for each test
and process should be maintained.

These inspections include :
• The specific methodology which will be used to test drug product.
• Complete assessment of laboratory compliance with GMP.
• Specific aspect of laboratory operations.
• Sop’s should be complete and adequate and laboratory operations must comply
with written procedures.
• Specifications and laboratory procedures should be suitable and as applicable ,
in conformance with application requirements.
• Inspections are designed to determine If the data Submitted in the application is
authentic And accurate, And the procedures in application Were used to
Produce the data contained in application.

 Material
 Method
 Man
 Machine

• This is also called as pre shipment inspection.
• This is the most popular type of QC inspection For importers.
• IT takes place when all the products are finished and ready for shipment.
• The samples are drawn in a random manner and is representive of whole
batch.
Statistical quality control
It is a technique of controlling quality of product by a set of statistical tools.
It consist of two key elements
1. Statistical process control(control charts )
2. Acceptance sampling(single sampling plan and double sampling plan)

 .
• Change control is a CGMP concept that focuses on managing
change to prevent unintended consequences. Certain
manufacturing changes (i.e changes that alter specifications, a
critical product attribute or bioavailability) require regulatory
filings and prior regulatory approval
• Change is an inherent part of the life cycle of a pharmaceutical
product. A change can be an addition to, deletion of, or
modification to manufacturing facility, utilities, process, material,
product, procedures or equipment (including software) which
impacts quality or regulatory requirements

 .
CHANGE CONTROL SYSTEM
• Change control is a procedure that ensures changes are
implemented in a controlled and coordinated manner.
• The change control program evaluate all changes that could affect
the production and control of the drug product, intermediate or API. It
is the most critical element in the overall quality management of
pharmaceutical industry.
• A change control system provides checks and balances in the
quality system by tracking, reviewing and approving the changes. In
adequate change control procedures ends up in regulatory non
compliance

CHANGES IN PHARMACEUTICAL OPERATIONS
INCLUDE
• Production : change in location , equipment , batch size, process control
parameters.
• Engineering : changes in Any part of equipment, design &layout , facility.
• Research & development : Change in specifications of raw materials ,
Quantity of raw materials,
Change in shelf life, environmental conditions, stability protocols , stability
conditions etc.
• Quality control : Change in Method of analysis, change in sampling plan
,change in Hardware /software of computerized instruments.
• Quality assurance : change in validation protocols , Sop‘s and documents
and sampling.
• Cleaning procedures : change in cleaning aids ,agents and procedures.

• A formal change control procedure always begins with a change proposal, which is
initiated by user department personnel with proper justification. The change
proposal then, evaluated by an expert team (change control committee)
contributing the appropriate expertise and knowledge from relevant areas.
• After change evaluation, quality unit will classify the change (i.e
minor/major/critical).
• Change classification triggers impact analysis of the proposed change for
identification of impacted systems and documents. There are several risk
associated with each change proposal, including reduced product quality.
• Risk assessment in changing requirements of existing systems is an important
aspect of producing the desired result of a change.

• After impact analysis and risk reduction, quality unit will approve or reject the
change proposal based on the criticality of the proposed change. The change
can be implemented after change approval by quality unit.
• After implementation, quality unit verify the effectiveness of implemented
changes, to confirm the change objectives were achieved and that there was no
deleterious impact on product quality. After verification of change implementation,
the change control can be closed.
• The change control is linked to other quality system such as CAPA, customer
complaints, validation etc.
• Includes criteria to evaluate whether changes affects regulatory filings.
• Includes evaluation criteria for determining if changes are technically justified.

GMP deficiencies related to change control
Inadequate review & approval of the change by
quality control unit.
Failure to file the changes with regulatory.
Failure to evaluate/justify the changes.
Excluding "like-for-like" changes from change
control program

1.0 Purpose : To provide instruction for change control procedure.
2.0 Objective : To provide a documented procedure for change
control procedure.
3.0 Scope : This procedure is applicable for change control
procedure.
4.0 Responsibility :
Primary: Officer / Supervisor of respective department.
Overall: Respective department Head.

5.0 PROCESS
• Components of change control
Following changes are including in change control procedure.
Change in the storage condition of raw material, finished goods, WIP.
Change in Expiry or retest date.
Change in Stability study protocol.
Change in SOP.
Change in protocol.
Change in Batch Manufacturing Record.
Change in Batch Packing Record.
Change in Specification and Analytical Test Method of following:
Raw materials and Packaging materials.
In process and Intermediates.
Finished Products.
Change in drawings.
Change in Utilities.
Change in Manufacturing process including rework and re-processing.
In process controls.

• Any of the changes excluding the changes in specifications, analytical methods,
Master Formula, Batch Manufacturing Records and those changes affecting the
regulatory affairs shall be controlled by the corporate QA.
• The person requesting the change should fill in the ‘Change Control form’ and
submit it to QA In charge through the department head.
• The person requesting the change shall add any reasons or justification with
adequate supporting data for the change to the ‘Change Control form”.
• The Q. A In charge shall evaluate the change proposal considering the necessity
for change and any other GMP aspects that will be affected by the proposed
change.
• If the Q.A In charge has the valid reasons to reject the proposal for change, he /
she can reject the change proposal and intimate the requester about the same.
• The Q.A In charge shall approve the change and shall forward the request to
corporate QA for their evaluation & suggestions if required.

• QA personnel shall coordinate with corporate QA for the
proposed change.
Once the QA department approves the change control
form, the user department shall prepare relevant revised
documents.
The revised document shall be approved by QA in
charge.
User department shall implement the change, based on
effective date mentioned on the documents.
6.0 DOCUMENTATION
• Change control form
• Change control log books.

• BENEFITS OF CHANGE CONTROL SYSTEM
• STRUCTURED AND SYSTEMATIC APPROACH FOR
CHANGE MANAGEMENT WITH PROPER CHANGE
EVALUATION
• DOCUMENTING & TRACKING THE DETAILS OF CHANGE
• ROUTING OF CHANGE REQUESTS TO APPROPRIATE
INDIVIDUALS/TEAM FOR APPROVALS
• DEMONSTRATE COMPLIANCE TO REGULATORY
AGENCIES.

Drug product inspection & change control

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