FDA Inspection Readiness

& Importance

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 HELLO!
I am Prasadhi.Shiva Shanker-Quality Assurance..
I am here because to share my Thoughts about

FDA Inspections Readiness & Importance.

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 DISCUSSION POINTS

What You’ll Learn

 PART-I
Basics of GMP/ About FDA & Its Regulations.

 PART-II
FDA Inspections and Inspection Management.

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 What are the GMPs?

 Good Manufacturing Practices or GMP is a system that consists of processes, procedures and
documentation that ensures manufacturing products, such as food, cosmetics, and
pharmaceutical goods, are consistently produced and controlled according to set quality
standards. Implementing GMP can help cut down on losses and waste, avoid recall, seizure.
 The CGMP requirements were established to be flexible in order to allow each manufacturer to
decide individually how to best implement the necessary controls by using scientifically sound
design, processing methods, and testing procedures.
 "C" in CGMP stands for "current," requiring companies to use technologies and systems that are
up-to-date in order to comply with the regulations.
 GMP guideline and Regulation address are the following areas [but not limited to]
Quality management / Sanitation and hygiene/Building and facilities /Equipment's /Raw materials
/ Personnel /Validation and qualification/Complaints /Documentation and recordkeeping
Inspections & quality audits etc.. 4
 Why are CGMPs so important?

 A consumer usually cannot detect (through smell, touch, or sight) that a drug product is
safe or if it will work.
 In most instances testing is done on a small sample of a batch (for example, a drug
manufacturer may test 100 tablets from a batch that contains 2 million tablets), so that
most of the batch can be used for patients rather than destroyed by testing.
 Therefore, it is important that drugs are manufactured under conditions and practices
required by the CGMP regulations to assure that quality is built into the design and
manufacturing process at every step.
 Facilities that are in good condition, equipment that is properly maintained and calibrated,
employees who are qualified and fully trained, and processes that are reliable and
reproducible, are a few examples of how CGMP requirements help to assure the safety and
efficacy of drug products. 5
 About Food and Drug Administration [FDA]..

 The Food and Drug Administration is the oldest comprehensive

consumer protection agency in the U. S. federal government.
 In the year 1848 the federal government has used chemical analysis
to monitor the safety of agricultural products a responsibility
inherited by the Department of Agriculture in 1862 and later by the
FDA.
 Although it was not known by its present name until 1930, FDA’s
modern regulatory functions began with the passage of the 1906 Pure
Food and Drugs Act.
 Formed on: June 30, 1906 ; 116 years ago.
 Headquarters : Maryland, United States, near Washington.
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 Current FDA 25th Commissioner: Robert Califf [February 17, 2022]
 Federal Food, Drug, and Cosmetic Act
( FFDCA or FD&C Act)

1. Chapters I and II : Short Title and Definitions.

2. Chapter III : Prohibited Acts and Penalties.
3. Chapter IV : Food.
4. Chapter V : Drugs and Devices.
5. Chapter VI : Cosmetics.
6. Chapter VII : General Authority.
7. Chapter VIII : Imports and Exports.
8. Chapter IX : Tobacco Products.
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9. Chapter X : Miscellaneous
 About FDA Forms

 There are three basic forms used by the FDA during an inspections:
• Form 482 (Notice of inspection),
When the FDA begins an inspection, a Form 482 will be presented, The 482 is issued to the organization’s
top management official or the most responsible person at the site at the time of the inspection.
• Form 483 (Inspectional observations),
The Form 483 lists observations made by the FDA representative(s) during the inspection. the 483 formally
notifies the organization’s top management of objectionable conditions relating to violations that were
observed during the inspection.
• Form 484 (Receipt for samples),
The Form 484 is issued at the end of an inspection describing any samples obtained during the
inspection.
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 FDA Inspection Types

1. Pre-Approval Inspection.
Pre-Approval Inspections are conducted after a company submits an application to FDA to
market a new product. These inspections focus on verifying data included in the application,
and confirming that the facility is capable of manufacturing said product. The outcome of a
pre-approval inspection is that inspectors will recommend for FDA approval.
2. Routine Inspections.
Routine Inspections are mandated by law every 2 years for class II and class III drug
manufacturers. They follow a prescribed method known as Quality System Inspection
Technique (QSIT). If a serious public health risk is identified during a routine inspection, the
inspection type may then switch to a “for cause” inspection.

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 FDA Inspection Types

3. Compliance Follow-Up Inspections

Compliance Follow-Up Inspections review actions taken by a firm/manufacturer in response to
a previous inspection that resulted in significant 483 observations or a Warning Letter. A
compliance follow-up is conducted to verify the adequate correction of previous violations, to
document continuing violations, or to support future regulatory action.

4. For Cause Inspections

For Cause Inspections investigate a specific problem that has been reported to FDA. The
source of the report can be the manufacturer (e.g. Recall), consumer/user complaints. A “for
cause” inspection will focus on the particular issue, but can branch out to cover unrelated
elements of the firm’s operations.
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 FDA's Inspection Authority

Section 704(a)(1) of FDCA: [ FDAC- “Federal Food, Drug, and Cosmetic Act” ]
FDA is "authorized to enter, at reasonable times, any factory, warehouse, or establishment in which food,
drugs, devices, or cosmetics are manufactured, processed, packed, or held all pertinent equipment, finished
and unfinished materials, containers, and labeling therein”.

Section 704(b) of FDCA:

"Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other
establishment, and prior to leaving the premises, the officer or employee making the inspection shall give to
the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed
by him which, in his judgment, indicate that any food, drug, device, or cosmetic in such establishment
consists in whole or in part of any filthy, or decomposed substance, or has been prepared, packed, or held
under insanitary conditions whereby it may have become contaminated with filth,
or whereby it may have been rendered injurious to health.
A copy of such report shall be sent promptly to the Company Secretary." 11
 Potential Post-Inspection Enforcement Actions

Inside US Outside US
- 483/EIR - 483/EIR
- Warning Latter - Warning Latter
- Injunctions [Court] - Import Detention
- Seizures Court
- Application Integrity Policy
- Criminal Investigation
Post Inspection Enforcement Actions
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 How does FDA determine if a company is
complying with cGMP regulations?

 FDA inspects pharmaceutical manufacturing facilities worldwide using scientifically and

cGMP-trained individuals whose job is to evaluate whether the company is following cGMP
regulations.

 FDA also depend on upon reports of potentially defective drug products from the public and
the industry.

 FDA will frequently use these reports to identify sites for which an inspection or
investigation is needed. [But not limited to..]

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 If a manufacturer is not following cGMPs, are drug
products safe for use?

 If a company is not complying with CGMP regulations, any drug it makes is considered
“adulterated” under the law. This kind of adulteration means that the drug was not
manufactured under conditions that comply with CGMP. It does not mean that there is
necessarily something wrong with the drug.
 “A drug or device shall be deemed to be adulterated … if it is a drug and the methods used
in, or the facilities or controls used for, its manufacture, processing, packaging, or holding
do not conform to or are not operated or administered in conformity with current good
manufacturing practice to assure that such drug meets the requirements of this chapter as
to safety and has the identity and strength, and meets the quality and purity characteristics,
which it purports or is represented to possess.”
As per FFDCA, Section 501(a)(2)(B)(2)- i.e Adulterated
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 What can FDA do to protect the public when there are
CGMP violations?

 If the failure to meet cGMPs results in the distribution of a defective drug, the company may
subsequently recall that product. Removing these drugs from the market protects the
public. While FDA cannot force a company to recall a drug, companies will usually recall
voluntarily or at FDA’s request. If a company refuses to recall a drug, FDA can warn the
public and may seize the drugs that are on the market.

 If the failure to meet cGMPs results in the distribution of a defective drug, the company may
subsequently recall that product. Removing these drugs from the market protects the
public. While FDA cannot force a company to recall a drug, companies will usually recall
voluntarily or at FDA’s request. If a company refuses to recall a drug, FDA can warn the
public and may seize the drugs that are on the market.
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 What can FDA do to protect the public when there are
CGMP violations?

 The Code of Federal Regulations (CFR) is divided into 50 titles that represent broad are as
subject to Federal regulations. Section 21 of the CFR contains most regulations pertaining
to food and drugs. Drug manufacturers are required to comply with the following cGMP
code of federal regulations.

 21 Code of Federal Regulations Part 210 (21 CFR 210): Current Good Manufacturing
Practice in Manufacturing Processing, packing, or Holding of Drugs.

 21 Code of Federal Regulations Part 211 (21 CFR 211): Current Good Manufacturing
Practice for Finished Pharmaceuticals.

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 FDA Regulation Into Company Quality System

ANPR: Advance notice of proposed rulemaking 17

 PART-II
Readiness / Preparation FDA inspections

Avoid risk Maintain audit readiness Achieve Process Excellence

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 Seven Most Important FDA Compliance Principles

1. Make FDA inspection procedures clear and with brief.

2. Make key documents & records easily accessible in an inspection-ready folder.
3. Label items for fast retrieval.
4. Compile complaints and CAPAs since your last inspection.
5. Report all corrections/recalls & keep documentation current.
6. Run mock FDA inspections to ensure preparedness.
7. Pro-active management of compliance initiatives and responses to Agency
enforcement activities. 19
 FDA Systems Inspection

1. Quality System:
This system assures overall compliance with cGMPs, internal procedures, and specifications. The system
includes the quality control unit and all of its review and approval (e.g., change control, reprocessing, batch
release, annual record review, validation protocols, and reports, etc.). It includes all product defect
evaluations and evaluation of returned drug products
(Refer the cGMP Regulation, 21 CFR 211 Subparts B, E, F, G, I, J, and K).

2. Facilities and Equipment System:

This system includes the measures and activities that provide an appropriate physical environment and
resources used in the production of the drugs or drug products. It includes buildings and facilities,
equipment qualifications, cleaning and validation of cleaning processes. Process performance qualification
of the overall process validation, heating, ventilation, and air conditioning (HVAC), compressed gases, steam,
and water systems
(Refer the cGMP Regulation, 21 CFR 211 Subparts B, C, D, and J). 20
 FDA Systems Inspection

3. Materials System:
This system includes measures and activities to control finished products, components, including water or
gases, which are incorporated into the product, containers and closures. It includes validation of
computerized inventory control processes, drug storage distribution controls, and records.
(Refer the cGMP Regulation, 21 CFR 211 Subparts B, E, H, and J).

4. Production System:
This system includes measures and activities to control the manufacture of drugs and drug products
including batch compounding, dosage form production, in-process sampling and testing, process validation.
It also includes establishing, following, and documenting the performance of approved manufacturing
procedures.
(Refer the cGMP regulation, 21 CFR 211 Subparts B, F, and J).

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 FDA Systems Inspection

5. Packaging and Labeling System:

This system includes measures and activities that control the packaging and labeling of drugs and drug
products. It includes written procedures, label examination and usage, label storage and issuance, packaging
and labeling operations controls.
(Refer the cGMP regulation, 21 CFR 211 Subparts B, G, and J).

6. Laboratory Control System:

This system includes measures and activities related to laboratory procedures, testing, analytical methods
development and validation or verification, and the stability program.
(Refer the cGMP regulation, 21 CFR 211 Subparts B, I, J, and K)

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Core Readiness Principle [but not limited..]

Quality System Adequacy.

Management Responsibility / Accountability.

Product / Process Control, Framework, e.g.
validation, batch records etc.
CAPA Management (CAPA).

Physical Plant / Personnel Capabilities.

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 What Comprises A Quality System?

 Your staff and how your staff is organized.

 The defined roles and responsibilities of your staff.
 Your decision-making models.
 Your quality manual and quality standards/policies.
 Your procedures and work instructions, i.e. SOPs
 Your electronic and paper-based records.
 All elements of your Quality System.
 In essence, almost EVERYTHING you do in Operations including Procurement, Quality,
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Regulatory and Storage and Distribution
 What FDA Compliance Expectations..?

 Strong executive management ownership and oversight.

 Ensuring operations associated with all systems are appropriately planned, approved,
conducted, and monitored.
 Ensuring that controls are implemented and completed satisfactorily during
manufacturing operations.
 Ensuring that developed procedures and specifications are appropriate and followed,
including those used by a firm under contract to the manufacturer.
 Approving or rejecting incoming materials, in-process materials, and drug products.
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 What FDA Quality System Focus..
Quality Systems [but not limited]
 CAPAs & OOSs thoroughly investigated, documented. Timely
Closed.
 FDA Enforcement commitments fully completed, documented.
 Well-designed documented structure i.e. SOPs, Policies, standards  Regular Mock inspections.
etc. that are widely distributed and followed.
 Any Significant Quality Issues thoroughly investigated, with
detailed well-written reports.
 Well structured, robust employee training and qualification
program.
 Well defined matrices for important measures with trend and
actions and actions to address negative trends
Inspections [but not limited]
 All employees trained regularly on inspection
management.
 Responsible individual for Ever Ready status.
 Pre-defined list of records, documents gather,
review, make ready upon arrival at facility.
 SMEs defined, Prepared, Challenged.
 Comprehensive Opening presentation for
operational review.
 Well-defined inspection plan.
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 FDA Inspection Management..

 Notice given by FDA

# If notice given, facility, documents, records, etc. should be "perfect"
 Form FDA-482
 Assemble - FAST!
# Inspection plans are triggered.
# Personnel notified inspection roles shall be taken.
#Communication plans put in place.
 Create and build Trust.
 Be helpful, facilitate the process.
 Do not "play ignorant" when a gap is observed during the inspection assume responsibility.

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 Inspection Management..Continue..

 Opening presentation.
# Consider "technical overview" for products
# Process flow diagrams
# Facility layout diagrams - use color, easy to read, etc.
 Copyists, runners, Backroom members (Separate Training Required)
# Do not bring originals
# Never leave Investigator alone with SME!
# Do in advance where Investigator is going.
 SMEs
# FDA can, and will, request "live review" of documents/records in IT tools used for various QA
System elements
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 Be responsive [ Clarify if unclear & Give what the investigator requests ]
 Inspection Management..[Investigators].

 Investigators are fact gatherers & reporters

 They are gathering evidence to support "case"
# Adulterated product / # Illegal products / # Documents / # Pictures
 Never underestimate an FDA Investigator - They are trying to create a "negative inference" about your operation
 Investigators are HIGHLY inconsistent from inspection experience!
 Investigators are trained to look for problems to determine to gain feeling of level of control
# CAPAs / Investigations/ # Rework / Reprocessing / Rejects/ # Complaints /
# Lab Investigations / OOS – OOT / # Returned Goods / Servicing / # Change Request Volumes
# Process Validation / Verification Reports [But not limited to ]
 Live Data Review and ensure the procedure and practice.

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 Inspection Management..[Investigators].

 Daily conduct
# Investigator won't give agenda.
# May or may not do wrap-up daily
# Must have procedure to prevent picture taking polices.
# Samples get logged
 Closeout
# Senior Management present
# If any observations are noticed Form 483 to most senior management.
# Response is CENTRAL - Within 15 Days!

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Together Everyone Achieve More

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“ " IF YOU'RE NOT WILLING TO LEARN,
NO ONE CAN HELP YOU .
IF YOU'RE STRONG-MINDED TO LEARN,
NO ONE CAN STOP YOU"

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 THANKS!
Any questions?
You can find me at
Shivashanker.p@sailife.com
+91 998 996 1747

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