1.

Current Good Manufacturing Practices

GOOD REGULATORY PRACTICES (MRA 101T)

Unit -1

Shyam Khante
Poona College of Pharmacy
 cGMP: INTRODUCTION
GMP should be “Designed” to be flexible to allow each manufacturer to
decide individually how to implement the necessary controls by using
scientific sound design, processing methods and testing procedures.

The “C” in GMP means current – up to date technologies

Overall concept:

Quality should be built into the product. Testing alone cannot be relied
on to ensure product quality A product that is ‘fit for its purpose”

GMP is a part of quality management which ensure that

products are consistently produced & controlled to the quality
standards appropriate to their intended use.

GMP is designed to minimize the risks involved in any

pharmaceutical production that cannot be eliminated through
testing the final product.

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 cGMP: Principle
• Build QUALITY in - you cannot test or inspect quality in to a product – it
must first be quality

• Have controls in place for each step of the process – increase the
likelihood the product produced in safe and fit for its intended purpose.

• Prevent the product from contamination and cross-contamination and

prevent mix-ups.

• Know what you are doing in advance and document what really happened
(document everything)

• Work towards consistency and control and monitor your system

• Have an independent Quality Assurance Group

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 cGMP: Global
It is influenced by international bodies

• ICH

• International Organization for Standardization (ISO)

• cGMP Harmonization Analysis working group (FDA 2003) Modify

21CFR210 and 211 to meet ICH

CFR: Code of Federal Regulations

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 21CFR11?

21CFR = FDA, Code of Federal Regulations

21CFR58 = GLP
21CFR210 = GMP, Drugs (General)
21CFR211 = GMP, Drugs (Finished Pharmaceuticals)
21CFR312 = Investigation New drug Application.. IND (GCP)
21CFR314 = FDA Approval of new drug NDA (GCP)
21CFR6xx = GMP, biologics
21CFR820 = GMP, Devices
21CFR…… = Food, nutrients and cosmetics
21CFR11 = Electronic Records; Electronic Signatures

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 cGMP: Global
• Non-biologics – FD&C Act section 501(a)(2)(b)

• Finished Pharmaceuticals – 21CFR211 – Clinical supply dosage forms

(including placebo) and commercially marketed dosage form

• ICH Q7A GMP for Active Pharmaceutical Ingredients

• Biologic Drug Products – 21CFR 210 and 211; 21CFR 600-680; comply
with BLA commitments and applicable standards

• Quality Systems - ISO9000, non-US Pharmaceutical quality management

requirements FDA Quality Requirement System (QRS)

• Guidance and CPGM (Compliance Program Guidance Manuals) – for FDA

GMP inspections – details cleaning validation, water systems,
microbiological and QC labs, sterile bulk substance

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 cGMP: Requirements

• A Quality System (change control, validation, CAPA)

• Qualified and trained personnel
• Fit for use buildings and facilities to meet the purpose
• Equipment that is suitable, clean, maintained and calibrated
• Controls in place to prevent degradation or contamination of materials
(raw, in process and final)
• Production and in-process controls for performance monitoring and
deviations
• Proper packaging and labeling – ID and Protection
• Laboratory controls – specifications , samples, testing

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 cGMP Violations - Severe Consequences
⚫ Product is “adulterated”
⚫ Shutdown of manufacturing facility
⚫ Seizure of product
⚫ Recall product
⚫ Front page press coverage
⚫ Competitive disadvantage
⚫ 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
❖ United States ex rel. King
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 cGMP: Raw Materials

• Active ingredients
• Excipients
• Audit suppliers on regular basis
✔ Before entering into contract, review regulatory history
✔ Monitor regulatory compliance
• Test incoming raw material

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 cGMP: Quality Conrol

“Q.C. is the part of GMP concerned with sampling, specifications, and testing as
well as documentation and release procedures which ensure that the necessary and
relevant tests are actually carried out and that materials are not released for use, nor
products released for sale or supply, until their quality has been satisfactory. Q.C. is
not confined to laboratory operations but must be involved in all decisions,
concerning the quality of the product”. (W.H.O.)

⮚Regulatory Guidelines on Quality Control:-

• The finished products must contain ingredients complying with the qualitative
and quantitative composition of the product described in the marketing
authorization.

• No batch of product is to be released for sale or supply prior to certification by

the authorized person(s) that it is in accordance with the requirements of the
marketing authorization.

• Sufficient samples of starting materials and products must be retained to permit

10 future examination of the product if necessary
 cGMP: Buildings and Facilities

• Separate or defined areas as are necessary to prevent contamination or mixups

• Air filtration systems (HVAC) in production areas
• Sanitation
(21 C.F.R. 211.110)

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 cGMP: Production and Process Controls (“SOPs”)

• 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.

(21 C.F.R. 211.110)

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 cGMP: In Process Testing

• 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
(21 C.F.R. 211.110)

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 cGMP: Expiration Dating

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 cGMP: Packaging and Labeling Operations

• Company must have written procedures designed to assure that correct labels,
labeling and packaging materials are used for drug products; such written
procedures shall be followed.
• Label mix ups have been a major reason for drug product recalls.

(21 C.F.R. 211.130)

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 cGMP: Laboratory Controls

• Testing and release for distribution

• For each batch of drug product, there shall be laboratory determination of
satisfactory conformance to final specifications for the drug product, including
the identity and strength of each active ingredient prior to release.
• There shall be appropriate laboratory testing, as necessary, of each batch required
to be free of objectionable microorganisms.
[21 C.F.R. 211.165 (a) & (b)]

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 cGMP: 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.
(21 C.F.R. 211.166)

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 cGMP: Production Record Review

• 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
(21 C.F.R. 211.192)

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 cGMP: Deviation Investigations

• 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 drug product
✔ Investigate other drug 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

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 cGMP: Deviation Investigations

• Corrective and Preventative Action Program

✔ As part of deviation investigations...
✔ Root cause identification and definitive corrective actions
• Company Program / System should audit:
✔ Timeliness of corrective / preventative actions
✔ Effectiveness of actions
✔ Documentation
Example:
Environmental monitoring/Cleaning

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 cGMP: Responsibility and Authority of Quality Control

Quality control unit “shall have the responsibility and authority to approve or
reject all components, drug product containers, closures, in-process materials,
packaging material, labeling, and drug 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 drug products manufactured,
processed, packed, or held under contract by another company.”

21 CFR 211.22(a)

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 cGMP: Complaints

• 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 Drug Experience report assessment
• Documentation of complaint and investigation or reason for not investigating

(21 C.F.R. 211.198)

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 cGMP: Records and Reports

• Contemporaneous documentation critical

✔ Laboratory and production records
✔ Trending analysis
• Data Integrity
• Internal review: OOS results, complaints, R&D
• External review: FDA inspections, business deals (due diligence), and
products liability cases

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 cGMP: Reports

• Field Alert Reports § 314.81(b)(1)

✔ Labeling
✔ Failure to meet specifications — STABILITY FAILURES
✔ Within 3 working days of receipt
✔ Warner Lambert criminal case
• Adverse Drug Experience Reports § 314.80
✔ ASAP but no later than 15 calendar days of initial receipt
✔ Foreign and domestic
• Recall Procedures and Preparation

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 cGMP: Auditing

• Independent Audit Group

❖ Resources
❖ Authority
• Global Approach - Harmonization of Quality Standards
• Audit priority systems / specific issues
• Follow-up audits

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 Modifications of Commission Directive 91/356/EEC of 13 June 1991 laying
down the principles and guidelines of good manufacturing practice for
medicinal products for human use

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 CHAPTER I

General provisions
Article 1
This Directive lays down the principles and guidelines of good manufacturing
practice for medicinal products for human use whose manufacture requires the
authorisation referred to in Article 16 of Directive 75/319/EEC

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 CHAPTER I

General provisions
Article 2
For the purposes of this Directive, the definition of medicinal products set out in
Article 1 (2) of Council Directive 65/65/EEC (3 ), shall apply
In addition,
- manufacture shall mean any holder of the authorisation referred to in Article
16 of Directive 75/319/EEC.
- qualified person shall mean the person referred to in Article 21 of Directive
75/319/EEC,
- pharmaceutical quality assurance shall mean the sum total of the organised
arrangements made with the object of ensuring that medicinal products are
of the quality required for their intended use,
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 CHAPTER I

General provisions
Article 2
-good manufacturing practice shall mean the part of quality assurance which
ensures that products are consistently produced and controlled to the quality
standards appropriate to their intended use

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 CHAPTER I

General provisions
Article 3
By means of the repeated inspections referred to in Article 26 of Directive
75/.319/EEC, the Member States shall ensure that manufacturers respect the
principles and guidelines of good manufacturing practice laid down by this
Directive.

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 CHAPTER I

General provisions
Article 4
The manufacturer shall ensure that the manufacturing operations are carried
out in accordance with good manufacturing practice and with the manufacturing
authorization.
For medicinal products imported from third countries, the importer shall ensure
that the medicinal products have been manufactured by manufacturers duly
authorized and conforming to good manufacturing practice standards, at least
equivalent to those laid down by the Community.

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 CHAPTER I

General provisions
Article 5
- The manufacturer shall ensure that all manufacturing operations subject to an
authorisation for marketing are carried out in accordance with the information
given in the application for marketing authorization as accepted by the
competent authorities
- The manufacture shall regularly review their manufacturing methods in the
light of scientific and technical progress. When a modification to the marketing
authorisation dossier is necessary, the application for modification must be
submitted to the competent authorities.

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 CHAPTER I

General provisions
Article 6
-The manufacturer shall establish and implement an effective pharmaceutical.
quality assurance system, involving the active participation of the management
and personnel of the different services involved.

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 CHAPTER I

General provisions
Article 7
Personnel
1. At each manufacturing site, the manufacturer shall have competent and appropriately
qualified personnel at his disposal in sufficient number to achieve the pharmaceutical
quality assurance objective.
2. The duties of managerial and supervisory staff, including the qualified person(s),
responsible for implementing and operating good manufacturing practice shall be
defined in job descriptions. Their hierarchical relationships shall be defined in an
organisation chart. Organisation charts and job descriptions shall be approved in
accordance with the manufacturer's internal procedures.
3. Staff referred to in paragraph 2 shall be given sufficient authority to discharge their
responsibility correctly.
4. Personnel shall receive initial and continuing training including the theory and
application of the concept of quality assurance and good manufacturing practice.
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 CHAPTER I

General provisions
Article 8
Premises and equipment
1. Premises and manufacturing equipment shall be located, designed, constructed,
adapted and maintained to suit the intended operations.
2. Lay out, design and operation must aim to minimise the risk of errors and permit
effective cleaning and maintenance in order to avoid contamination, cross
contamination and, in general, any adverse effect on the quality of the product.
3. Premises and equipment intended to be used for manufacturing operations which are
critical for the quality of the products shall be subjected to appropriate qualification.

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 CHAPTER I
General provisions
Article 9
Documentation
1. The manufacturer shall have a system of documentation based upon
specifications, manufacturing formulae and processing and packaging
instructions, procedures and records covering the various manufacturing
operations that they perform. Documents shall be clear, free from errors and
kept up to date. Pre-established procedures for general manufacturing
operations and conditions shall be available, together with specific
documents for the manufacture of each batch. This set of documents shall
make it possible to trace the history of the manufacture of each batch. The
batch documentation shall be retained for at least one year after the expiry
date of the batches to which it relates or at least five years after the
certification referred to in Article 22(2) of Directive 75/319/EEC whichever is
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the longer.
 CHAPTER I
General provisions
Article 9
Documentation
2. When electronic, photographic or other data processing systems are used
instead of written documents, the manufacturer shall have validated the
systems by proving that the data will be appropriately stored during the
anticipated period of storage. Data stored by these systems shall be made
readily available in legible form.
3. The electronically stored data shall be protected against loss or damage of
data (e.g. by duplication or backup and transfer onto another storage system).

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 CHAPTER I
General provisions
Article 10
Production
-The different production operations shall be carried out according to pre-
established instructions and procedures and in accordance with good
manufacturing practice. Adequate and sufficient resources shall be made
available for the in-process controls. Appropriate technical and/or organisational
measures shall be taken to avoid cross contamination and mix-ups.
- Any new manufacture or important modification of a manufacturing process
shall be validated. Critical phases of manufacturing processes shall be regularly
revalidated.

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 CHAPTER I
General provisions
Article 11
Quality Control
1. The manufacturer shall establish and maintain a quality control department.
This department shall be placed under the authority of a person having the
required qualifications and shall be independent of the other departments.
2. The quality control department shall have at its disposal one or more quality
control laboratories appropriately staffed and equipped to carry out the
necessary examination and testing of starting materials, packaging
materials and intermediate and finished products testing. Resorting to
outside laboratories may be authorised in accordance with Article 12 of this
Directive after the authorisation referred to in Article 5b of Directive
75/319/EEC has been granted.

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 CHAPTER I
General provisions
Article 11
Quality Control
3. During the final control of finished products before their release for sale or
distribution, in addition to analytical results, the quality control department shall
take into account essential information such as the production conditions, the
results of in-process controls, the examination of the manufacturing documents
and the conformity of the products to their specifications (including the final
finished pack).
4. Samples of each batch of finished products shall be retained for at least one
year after the expiry date.
5. Unless in the Member States of manufacture a longer period is required,
samples of starting materials (other than solvents, gases and water) used shall
be retained for at lest two years after the release of the product.

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 CHAPTER I
General provisions
Article 12
Work contracted out
1. Any manufacturing operation or operation linked with the manufacture which
is carried out under contract, shall be the subject of a written contract
between the contract giver and the contract acceptor.
2. The contract shall clearly define the responsibilities of each party and in
particular the observance of good manufacturing practice by the contract
acceptor and the manner in which the qualified person responsible for releasing
each batch shall undertake his full responsibilities.
3. The contract acceptor shall not subcontract any of the work entrusted to him
by the contract giver without the written authorisation of the contract giver.
4. The contract acceptor shall respect the principles and guidelines of good
manufacturing practice and shall submit to inspections carried out by the
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competent authorities as provided for by Article 26 of Directive 75/319/EEC.
 CHAPTER I
General provisions
Article 13
Complaints and product recall
- The manufacture shall implement a system for recording and reviewing
complaints together with an effective system for recalling promptly and at any
time the medicinal products in the distribution network.
- Any complaint concerning a defect shall be recorded and investigated by the
manufacturer. The competent authority shall be informed by the manufacturer
of any defect that could result in a recall or abnormal restriction on the supply.
In so far as possible, the countries of destination shall also be indicated.

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 Final Provisions
Article 14
Self-inspection
-Member States shall bring into force the laws, regulations and administrative
provisions necessary to comply with this Directive not later than 1 January
1992. They shall forthwith inform the Commission thereof.

-When Member States adopt these provisions, these shall contain a reference
to this Directive or shall be accompanied by such reference at the time of their
official publication. The procedure for such reference shall be adopted by
Member States.

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