cGMP TRAINING

SUNTARA COSMETICS PVT. LTD.

PREPARED BY:
PRATHAM CONSULTANTS

CONFIDENTIAL
• cGMP Introduction
• cGMP Violations – Severe Consequences
• cGMP – Current Trends
• Buildings & Facilities
• Equipments
• Control of Components, Containers and Closures.
• Production and Process Controls
• Packaging and Labeling Controls
• Holding and Distribution
• Laboratory Controls and Stability Testing

CONFIDENTIAL
• Water System
• Clean Area Classification / HVAC
• Validation
• Quality Management System
• Product Quality Review / Annual Product Quality Review
• OOS / Deviations / CAR / Investigations
• Records and Reports
• Complaints Returned and Salvaged Products Auditing
• Self Inspection
• Sanitation and Hygiene

CONFIDENTIAL
• WHO defines GMP as:
– GMP is that part of quality assurance which ensures that products are
consistently produced and controlled to the quality standards appropriate
to their intended use and as required by the marketing authorization“
• USFDA: GMP comprises of Six Systems:

• MHRA Defines GMP as:

– GMP means the part of quality assurance which ensures that the
products are consistently produced and controlled in accordance with
the quality standards appropriate to their intended use.
CONFIDENTIAL
• 10 COMMANDMENTS OF GMP:
– Write Procedures.
– Follow Thy Written Procedures.
– Document/Record Thy Work.
– Validate Thy Work.
– Design & Build Proper Facilities & Equipment.
– Maintain Thy Facilities And Equipment
– Be Competent.
– Be Clean
– Control For Quality.
– Audit For Compliance.

CONFIDENTIAL
• OVERVIEW OF GMP SCOPE:

CONFIDENTIAL
I) Product is “adulterated”

II) Shutdown of manufacturing facility

III) Seizure of product

IV) Recall product

V) Front page press coverage

VI) Competitive disadvantage

CONFIDENTIAL
• GMP Hold on product applications
– International sites

• Injunction / Consent decree

– Schering Plough ($500 Million)
– Abbott Laboratories ($100 Million)
– Wyeth–Ayerst Laboratories ($30 Million)
– Individual Defendants

• Criminal Investigations and Indictments

• Lawsuits

CONFIDENTIAL
• 21st Century: Risk-Based Approach
– Risk-based assessment
– Up-to-date Science-based policies and standards

• Integrated Systems approach

– Quality / Facilities and Equipment / Materials / Production

• International cooperation
– International Conference on Harmonization

• Proposed amendments regarding validation and cross-

contamination
CONFIDENTIAL
• All manufacturing processes are clearly defined, systematically
reviewed in the light of experience and shown to be capable of
consistently manufacturing cosmetic products of the required
quality and complying with their specifications;
• Critical steps of manufacturing processes and significant changes to
the process are validated;
• All necessary facilities for GMP are provided including:
– appropriately qualified and trained personnel;
– adequate premises and space;
– suitable equipment and services;
– approved procedures and instructions;
– suitable storage and transport
– correct materials, containers and labels;
• Instructions and procedures are written in an instructional form in clear
and unambiguous language, specifically applicable to the facilities
provided;
• Operators are trained to carry out procedures correctly;
• Records are made, manually and/or by recording instruments, during
manufacture which demonstrate that all the steps required by the
defined procedures and instructions were in fact taken and that the
quantity and quality of the product was as expected. Any significant
deviations are fully recorded and investigated.
• Records of manufacture including distribution which enable the
complete history of a batch to be traced, are retained in a
comprehensible and accessible form;
• The distribution (wholesaling) of the products minimizes any risk
to their quality;
• A system is available to recall any batch of product, from sale or
supply;
• Complaints about marketed products are examined, the causes
of quality defects investigated and appropriate measures taken in
respect of the defective products and to prevent reoccurrence
• Buildings shall be….suitable
• Operations to be in specifically defined areas...separate…Or such
• Other control systems for ….operations as are necessary to
prevent contamination or mix-ups….
• Building….shall be….clean and tidy.
– Separate or defined areas as are necessary to prevent contamination or
mix-ups.
• All necessary facilities/resources for GMP should be provided :
– Adequate, qualified and well-trained personnel
– Suitable premises and sufficient space
– Suitable location
– Good personal hygiene and proper sanitation
– Suitable equipment and services
 I) Design and construction features

II) Lighting

III) Ventilation, air filtration, air heating and cooling

IV) Plumbing

V) Sewage and refuse

VI) Washing and toilet facilities

VII) Sanitation

VIII) Maintenance
• The main principle for equipment should be that it is easy to
dismantle or remove to facilitate cleaning by non-corrosive
materials.
• Design, type, size and installation of equipment shall be in such
a way as to avoid and prevent any contamination during use.
• When choosing and buying machines, hygienic production and
possibilities for cleaning and disinfection must be considered.
• Contamination is a leading cause of product failure.The
maintenance personnel and others involved in production need
to understand the destructive nature of contamination and
realize the benefits in removing contamination from their
facilities.
I) Equipment design, size, and location.

II) Equipment construction.

III) Equipment cleaning and maintenance.

IV) Automatic, mechanical, and electronic equipment.

V) Filters.

VI) Surfaces ….shall not be reactive, additive, or absorptive

VII) Equipment….shall be cleaned, maintained and sanitized….

• General requirements.
• Receipt & storage of untested components, product containers,
and closures.
• Testing and approval or rejection of components, product
containers, and closures.
• Use of approved components, product containers, and closures.
• Retesting of approved components, product containers, and
closures.
• Rejected components, product containers, and closures.
• Product containers and closures.
• Containers and closures ….handled in a manner to prevent
contamination.
• Must have written procedures and testing of product while
being manufactured to assure batch uniformity and integrity
• Control procedures shall be established to monitor output
and to validate manufacturing processes that could cause
variability
Production and control records shall be reviewed and
approved by the quality control unit to determine
compliance with all established, approved written
procedures before a batch is released or distributed.
– Product Impact Assessment
– Trend Analysis
– Distributed Product
• Written production and process control procedures shall be
followed in manufacturing and shall be documented at the time of
performance. Any deviation from these procedures shall be
recorded and explained or justified.
• Charge-in of components.
• Calculation of yield.
• Equipment identification.
• Sampling and testing of in-process materials and products.
• Time limitations on production.
• Control of microbiological contamination.
• Reprocessing.
• Company must have written procedures designed to assure that
correct labels, labeling and packaging materials are used for
cosmetic products; such written procedures shall be followed.
• Label mix ups have been a major reason for cosmetic product
recalls.
• Materials examination and usage criteria.
• Labeling issuance.
• Packaging and labeling operations.
• Cosmetic product inspection.
• Expiration dating.
 Warehousing procedures

Distribution procedures

Quarantine before release

Store under appropriate conditions

Quality control unit “shall have the responsibility and
authority to approve or reject all components, product
containers, closures, in-process materials, packaging material,
labeling, and products, and the authority to review production
records to assure that no errors have occurred or, if errors
have occurred, that they have been fully investigated. The
quality control unit shall be responsible for approving or
rejecting products manufactured, processed, packed, or held
under contract by another company.”
• General requirements.
• Testing and release for distribution.
– For each batch of cosmetic product, there shall be laboratory
determination of satisfactory conformance to final specifications for the
cosmetic product, including the identity and strength of each ingredient
prior to release.
– There shall be appropriate laboratory testing, as necessary, of each
batch required to be free of objectionable microorganisms.
• Stability testing.
Stability Testing
A written testing program designed to assess stability
characteristics is required. Stability testing results must be
used in determining storage conditions and expiration dates.

• Special testing requirements.

• Reserve samples.
• Laboratory animals.
• Product contamination.

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• Establish specs, standards, sampling plans, test procedures
Calibration, of laboratory equipment
• Adequate acceptance criteria
• Validate test methods
• Conduct stability program
• Special tests
• Keep reserve sample
• Product suppliers:
– Audit suppliers on regular basis
– Before entering into contract, review regulatory history
– Monitor regulatory compliance
 To assure that a Expiration dates shall be
cosmetic product meets related to any storage
applicable standards of conditions stated on the
identity, strength,
labeling, as determined
quality and purity at the
time of use, it shall bear by stability studies
an expiration date
determined by
appropriate stability
testing.
 QUALIFICATION PHASES
• Three phase approach recommended according to WHO Technical
Report Series 929 to prove reliability and robustness.
– Phase 1 (investigational phase)
– Phase 2 (verification step)
– Phase 3
• Over 1 year after the satisfactory completion of phase 2
• Water can be used for manufacturing purposes during this phase
• Demonstrate:
– Extended reliable performance
– That seasonal variations are evaluated
• Sample locations, sampling frequencies and tests should be reduced
to the normal routine pattern based on established procedures
proven during phases 1 and 2
FDA Guideline:
The FDA Guidance has a similar table to the EU GMP for the required
airborne particle and microbial conditions for hygienic processing.
However, the FDA place emphasis on ensuring that the processing areas
conform to the classification in the operational conditions. These
conditions are given in the following table:
Microbiological
Clean Area Microbiological
Setting Plates
Classification >= 0.5mm Active Air
ISO Designation Action Levels c,d
(0.5 mm particles/m3 Action Levels c
(diam. 90mm;
particles/ft3 (cfu/m3)
cfu/4hours)
100 4.8/ 5 3,520 1e 1e
1000 6 35,200 7 3
10,000 7 352,000 10 5
100,000 8 3,520,000 100 50
HEPA FILTERS:
• A throw-away extended- medium, dry type filter in a rigid
frame having minimum particle collection efficiency of 99.97 %
(i.e ,a maximum particle - penetration of 0.03%) for 0.3 micron
particles of thermally generated DOP or specified alternative
aerosol.
– Filter integrity test
– Air velocity/ air quantity/ acph measurment
– Non-viable airborne particle count test
– Viable particle count test
– Differential pressure monitoring
– Temperature & % RH monitoring
– Recovery study
– Smoke pattern test
• Definition
Validation is the documented act of proving that any procedure,
process, equipment, material, activity or system actually leads to the
expected result
• Essential Part of GMP
• Predetermined protocols
• Written reports
• Processes and procedures
• Periodic revalidation
• Specific attention:
– Processing
– Testing
– Cleaning
 Types of Process Validation
• Experimental approach
– Prospective validation Stages of Validation
– Concurrent validation Design qualification (DQ)
• Analysis of historical data Installation qualification (IQ)
– Retrospective validation Operational qualification (OQ)
• Revalidation Performance qualification (PQ)
– Periodic revalidation
– Revalidation after change
• The Validation Master Plan could consist of:
– Approval page and table of contents
– Introduction and objectives
– Facility and process description
– Personnel, planning and scheduling
– Responsibilities of committee members
– Process control aspects
– Equipment, apparatus, processes and systems to be validated
– Acceptance criteria
– Documentation e.g.validation protocols and reports
– SOPs
– Training requirements
Quality Management

Quality Assurance

GMP

Quality Control
What is Quality Management ?
• The aspect of management function that determines &
implements the “quality policy”
• The overall intention & direction regarding quality, as formally
expressed & authorized by top management
• The attainment of this quality objective
should be led by the senior management &
requires the participation and commitment
by staff, by the company’s suppliers and
distributors.
• To achieve the reliable quality objective,
there should be a comprehensive QA system
incorporating GMP.
• The QA system should be fully documented
& its effectiveness should be monitored.
• Quality Assurance
• QA covers all matters which individually or collectively influence
the quality of a product.
• All parts of QA system should be adequately resourced with:
– Competent personnel
– Suitable & sufficient premises, equipment & facilities
• Wide-ranging concept
– Covers all matters that individually or collectively influence the
quality of a product
• Totality of the arrangements
– To ensure that the product is of the right quality for the intended use
• QA incorporates GMP
– Supports product design & development
• Ensure that products are designed and developed based on sound
scientific rationale and with GMP or GLP principles being taken
into consideration.

• Ensure that managerial responsibilities are clearly specified.

• Ensure that production and control operations are clearly

specified and GMP is adopted.
• Organize supply & use of correct starting & packaging materials.
• Ensure that finished products are correctly processed & checked before
release.
• Ensure that products are released after review by authorized person.
• Provide satisfactory arrangement to ensure products are stored,
distributed & handled appropriately.
• Put in place a mechanism for regular self inspection / internal quality
audit.
• Part of QA which ensures that products are consistently produced and
controlled to the quality standards appropriate to their intended use.
• Minimize risks:
– Cross contamination
– Mix up
• All manufacturing process are clearly defined and
systematically reviewed.
– An appropriate infrastructure or “quality system” encompassing the
organization structure, procedures, processes and resources
– The systematic actions necessary to ensure adequate confidence that a
product (or service) will satisfy given requirements for “Quality”
– The totality of these actions is referred to as “Quality Assurance”
• Procedures for self-inspection and quality audits are applied
• Deviations are reported, investigated and recorded
• System for change control is applied
• Regular evaluation of product quality to verify consistency and
continued improvement
Objectives of Product Quality Review:
• To review and verify the consistency and appropriateness of
the existing process.
• To identify and highlight any trends in the process, e.g. in
analytical results, yields etc.
• To identify any possible product or process improvements
• Review of starting materials/ packaging materials, especially from
new sources
• Review of in-process control results and finished product
analytical control results
• Amount of batches and packaging units produced and their yields
• Reviews of:
– Out-of-spec situations, rejections, deviations, changes
– Plus investigations and analysis of causes
• Review of Marketing Authorization variations submitted,
granted or refused (incl. third countries)
• Review of stability programme and trends
• Review of adequacy of previous decisions on changes or
improvements or corrective actions
• For new Marketing Authorizations (plus new variations) a
review of post marketing commitment
• The qualification status of all relevant equipment and utilities
(like water, HVAC, gases, etc.)
• Review of Technical Agreements (if applicable)
 Begin Analytical process

Error identified? No Complete the

analytical process &
No
Stop the process and report results
Correct the error Data generated?

Suspect Result:
1. Notify Section Head
2. Keep samples and solutions Correct & re Assignable
calculate the results cause aberrant
testing.
Obvious calculation error

No Yes
Perform a minimum
of 3 testing
Assignable cause

Are repeat test results within

experimental error of original
Assign an OOS number No under limit results and all
and conduct a Formal
within specification?
Laboratory Investigation
Document average of repeat +
original passing results
• Thorough investigation:
– QC involved
– With special attention to establish whether "counterfeiting" may have been
the cause
– Fully recorded investigation – reflect all the details
• Due to product defect (discovered or suspected):
– Consider checking other batches
– Batches containing reprocessed product
• Investigation and evaluation should result in appropriate follow-
up actions
– May include a "recall"
• All decisions and measures taken should be recorded
• Referenced in batch records
• Records reviewed - trends and recurring problems
• Inform competent authorities in case of serious quality problems
such as:
– Faulty manufacture
– Product deterioration
– Counterfeiting
• Have a thorough recall procedure that is consistent with the
complaints handling procedure
• Trend complaints, their investigations and results
• Deviation shall be classified into 2 categories, namely, planned and
unplanned deviation.

– Planned deviation: A deviation from an established procedure, process or

method planned prior to execution, is classified as planned deviation.
Planned deviations are not meant to substitute the engineering or
documentation change control system. Planned deviations are by definition
restricted to specific period of time or specific number of batches.

– Unplanned deviation: Unplanned deviation is a deviation from a standard

procedure during execution of a process, method or procedure that could
have an impact on quality, safety, efficacy or purity of a drug product, or on
the efficiency of a process. All such deviations must be thoroughly
investigated and documented and will require corrective or preventive
action.
• Classification of Deviation
• Planned deviation and unplanned deviation shall be classified on
the basis of impact as Critical, Major and Minor deviation

A deviation that has substantial potential to have an adverse impact on the

Critical identity, strength, quality or potency of a product or produce a product which
is not in accordance with the specifications or customer requirement.
A deviation that may have impact on the identity, strength, quality or potency
Major of product which is not in accordance to standard specified but not from
customer requirement.
A deviation that may not have any adverse impact on the identity, strength,
Minor quality or potency of a product, it is due to a departure from approved
procedures.

Deviation shall be reported within 24 hrs .

• Any unexplained discrepancy or the failure of a batch or any of
its components to meet any of its specifications must be
investigated whether or not the batch has already been
distributed.
– Investigate other batches of same product
– Investigate other products that may have been associated with the
specific failure or discrepancy
– Written record of investigation
• Documenting the Investigation is Critical
– Hypotheses should be scientifically based
– Subject matter experts should be consulted throughout the
investigation, including the initial identification of Hypotheses.
– Once a hypothesis is identified, it must be investigated
– All hypotheses should be validated or invalidated
 CAR
• Correction: Corrections are to correct the situation and proceed
with the batch or the process. After verification of the correction
taken by the concerned department, the processing may be
allowed if the impact assessment done, clearly indicates that the
deviation occurred has not affected the product in terms of quality
and safety. Reasons for taking such decision by the authorized
person should be documented with his signatures.
 CAR
• Corrective Action: The corrective actions are to prevent the
deviation from occurring again. The corrective actions may take
time for implementation. Corrective actions may involve some
facility modification, procurement of equipment or any material,
resource planning. Still, a time line should be planned and
monitored for the implementation. The corrective actions planned
for one deviation, must be applied or extended to all the similar
systems, procedures, practices, equipment, operating areas, in
order to take a uniform approach for all related issues
Sources of CAR
Out of Out of
Change Specification calibration
control (OOS) ( OOC )
Deviation

Out of trend Self Supplier

( OOT)
Regulatory inspection Audits
Audits

Market
Complaints
Product And many more…
Withdrawal
and Recall
CAR
• CAR should cover all correction and corrective actions that
needs to be initiated and implemented as a result from
analyzing process, quality records, OOS, OOC, OOT, deviation,
Market complaint, Product withdrawal and recall, Audit
observations, Returned goods, OOS reported by contract
givers to identify existing or potential cause of non
conformance.
• QA to administer the CAR program, perform investigation and
track and trend CAR.
CAR
• The elements of the correction and corrective action program
are:
– Identifying problems that may require a correction action.
– Deciding if a correction action is required.
– Investigating and determining the root causes of the problem, and
proposing the correction action that will eliminate the non-conformity.
– Filling the Corrective Action Request Form. Obtaining the approval from
Quality Assurance for the proposed correction action before it is
executed.
CAR

• Correcting the problem by implementing the correction action to

eliminate the root causes of the non-conformity.
• Performing an Effectiveness Check, when applicable, to ensure
that implementation of the corrective action eliminated the root
causes of the non-conformity and will prevent it from re-
occurring. QA shall apply CAR Review checklist to confirm
appropriate results from CAR.
List of things that go wrong with failure investigations:
• Other perceived higher priority work takes precedence over the
conduct of the investigation.
– Investigation be conducted timely and on priority, identify and prevent the
future recurrence.
• Firm’s own investigation SOP is not followed.
• Various independent groups become involved in the process
without the assignment of responsibility or ownership
– GMPs specifically state that QC unit has the primary authority to assure
these situations are addressed, it is necessary that there be inputs by other
units. Information must be objectively evaluated and conclusions reached
before final Quality unit approval.
• Keep records, make available for inspection
• Conduct annual review of each product for changes to specs,
control procedures
• Keep equipment cleaning and use log
• Keep component, container, closure and labeling records
• Have SOP for master production and control record, maintain
record
• Use batch production and control records for manufacture, keep records
• Records to be reviewed/approved by quality control unit
• Complete data derived from all tests necessary to assure compliance
• Distribution records, with lot numbers(except medical gases)
• Complaint files
• Clear, written instructions and procedures
• Trained operators
• Records of actions, deviations and investigations
• Records for manufacture and distribution
• Proper storage and distribution
• Systems for complaints and recalls
• Records and Reports Production record review
– applies to prod. record review - requires any unexplained discrepancy to be
thoroughly investigated.
• Contemporaneous documentation critical
– Laboratory and production records
– Trending analysis
• Data Integrity
• Internal review: OOS results, complaints, R&D
• External review: Inspections, business deals (due diligence), and
products liability cases.
• Recall Procedures and Preparation
• If conditions cast doubt returned product shall be destroyed
unless proved ok by test, examination, investigation
• Salvage only if evidence from tests and inspection show all
standards met.

• Complaints: Principle
“All complaints and other information concerning potentially
defective products must be carefully reviewed according to
written procedures and corrective action should be taken.”
Designated responsible person:
• To handle complaint
• Decide on measure to be taken
• May be authorized person - if not, must advise authorized person
of results
• Sufficient support staff
• Access to records
• Written procedure (SOP):
• Describes action to be taken
• Includes need to consider a recall (e.g. possible product defect)
Written procedures describing the handling of all written and oral
complaints
Review by Quality Control unit
• Possible failure to meet any specification
• Determine need for deviation investigation
• Adverse Cosmetic Experience report assessment
Documentation of complaint and investigation or reason for not
investigating
Purpose is to evaluate whether a company’s operations remain
compliant with GMP

The programme should

• Cover all aspects of production and quality control
• Be designed to detect shortcomings in the implementation of GMP
• Recommend corrective actions
• Set a timetable for corrective action to be completed
• Should be performed routinely
• Also on special occasions such as Recalls &Repeated rejections
• Performed by team appointed by management, with:
– authority
– sufficient experience, expertise in their own field. knowledge of GMP
– may be from inside or outside the company
• Frequency should normally be at least once a year
– May depend on company requirements
– Size of the company and activities
• Report prepared at completion of inspection, including:
– results
– evaluation
– conclusions
– recommended corrective measures
• Follow-up action
– Effective follow-up programme
– Company management to evaluate both the report and corrective actions
 Objectives
• Review measures to ensure good
sanitation in:
– Premises and personnel
– Equipment and apparatus
– Processes, materials and containers
• To review measures to ensure good
personal hygiene
• Group session - to discuss the situation
in your country and to look at some bad
sanitation and hygiene practices
 Scope

• High level of sanitation and hygiene practised

– in every aspect of manufacturing. It covers:
– Personnel
– Premises
– Equipment and apparatus
– Production materials and containers
– Products for cleaning and disinfection
– All potential sources of cross-contamination
Personal Hygiene
• Health examinations:
– Before and during employment
– Periodic eye examinations for those who do visual
inspections

• Training:
– Practices in personal hygiene
– Written procedures and instructions
– Signs in areas
 Personal Hygiene

• Written procedures and instructions

- to wash hands before entering
production areas

• Some also use disinfectants

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Personal Hygiene
• Wash hands before entering production areas

• Signs in areas (e.g. changing rooms)

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Personal Hygiene
• Illness or open lesions:
– May affect the quality of products
– Should not handle starting materials, intermediates or
finished products.
– Instruction and encouragement to
report to supervisors

• Direct contact between product and operator:

– Should be avoided
– Starting materials, primary packaging materials,
intermediate and bulk product
Personal Hygiene
• Protection of product from contamination:
– Clean clothes appropriate to personnel activities
– Including hair covering (e.g. caps)

• Check change rooms/changing facilities

– Hand washing, signs, drying of hands
– Used clothing stored in separate closed containers while awaiting
cleaning
– Laundering of clean area clothing according to an SOP and in an
appropriate facility
– Procedure for disinfecting and sterilizing when required
Personal Hygiene
• Smoking, eating and drinking not allowed in production
areas, laboratories and storage areas
• No chewing (e.g. gum), or keeping food or drinks allowed
• No plants kept inside these areas
• Rest and refreshment areas should be separate from
manufacturing and control areas
• Toilets should not open directly into production or storage areas
• Personal hygiene procedures including wearing protective
clothing apply to all persons entering into production areas:
– Full-time employees
– Temporary workers
– Contractor's employees
– Visitors
– Managers
– Inspectors

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