A complete overview of Product Lifecycle Management on Pharmaceutical Industry

1. Presented by : Vikas
Rathee

2. Contents :
 Prior Approval Supplement (PAS)
 Post Approval Changes [SUPAC]
 Changes Being Effected in 30 Days (CBE-30)
 Annual Report
 Post marketing Reporting Requirements
 Post approval Labeling Changes
 Lifecycle Management
 FDA Inspection and Enforcement

3.  Warning Letters
 Recalls
 Seizures
 Injunctions
 ISO Risk Management Standard

4. Prior Approval Supplement
A major change requires the submission
of a supplement and approval by FDA
prior to distribution of drug product
This type of supplement is called, a
Prior Approval Supplement

5. Prior Approval Supplement
• Guidance provides recommendations:
• New drug applications (NDAs)
• Abbreviated new drug applications (ANDAs)
• They make postapproval changes (section 506A of
the Federal Food, Drug, and Cosmetic Act (the Act)
and § 314.70 (21 CFR 314.70).

6. Recommendations are provided for post approval
changes in :
1. Components and composition
2. Manufacturing sites
3. Manufacturing process
4. Specifications
5. Container closure system
6. Labeling
7. Miscellaneous changes
8. Multiple related changes.

7. Filing with the FDA to approval of a major change
may lead to adverse effect on:
1. Identity
2. Strength
3. Quality
4. Purity
5. Potency
These factors may relate to the safety or effectiveness
of the drug product.

8. SUPAC
• In the process of developing the new product, the
batch size used in earliest human studies are small.
• The sizes of the batch is gradually increased(scale
up).
• The scale up and the changes made after approval in
the composition manufacturing process ,
• manufacturing equipment
• change of site have become known as scale up and
post approval changes (supac)

9. 1. Supac-IR (immediate release solid oral dosage
form .
2. Supac-MR (for modified release solid oral doasage
form)
3. Supac-SS (for non sterile semisolid dosage form
including creams,ointements,gels and lotions)

10. SUPAC GUIDELINES DEFINES
• Minor
• Moderate
• Major
Level
• Annual report
• Changes being affected supplement
• Prior approval supplement
Filing
• Application/compendial tests
• In-vitro dissolution/release
• In-vivo
Test

11. Level of Changes
• Level 1: Those changes that are unlikely to have any
detectable impact on formulation quality and performance.
Example:
• Changes in the color, flavors
• Changes in the excipient express as the percentage (w/w) of
total formulation, less than or equal to the following range.
• Level 2: Changes are those that could have significant
impact on the formulation quality and performance. Example:
• Changes in the technical grade of excipient (Avicel PH102 vs.
Avicel PH200)
• Changes expressed as percent (w/w of total formulation)

12. • Level 3: Changes are those that are likely to have
significant impact on formulation quality and performance.

13. Changes Being Effected in 30 Days (CBE-30
supplement)
• CBE-30 supplement involves certain moderate changes that
require the submission of the supplement to FDA at least 30
days before the distribution of the drug product made using the
change.
• There are two types of moderate change. One type of
moderate change requires the submission of a supplement to
FDA at least 30 days before the distribution of the drug product
.
• This type of supplement is called, and should be clearly
labeled, a Supplement - Changes Being Effected in 30 Days
•

14. • If, after review, FDA disapproves supplement it may order
the manufacturer to cease distribution of the drug
products made using the disapproved change.

15. Annual report
The applicant must describe minor changes in its
Annual Report .
In annual reports, the list should be included in the
summary section.
Assessment of the Effects of the Change The holder of
an approved application under section 505 of the Act
must assess the effects of the change before
distributing a drug product.

16. General requirement
Postmarketing studies within the meaning of this section are
those that concern:
• (1)Clinical safety
• (2)Clinical efficacy
• (3)Clinical pharmacology
• (4)Nonclinical toxicology

17. What to report
1. Licensed biological product report to FDA ( status of
postmarketing studies- approved product application).
2. Annual progress report and transmittal Form FDA-2252.

18. POST-MARKETING REPORTING
REQUIREMENTS
Required for all studies and clinical trials
For assessing or identifying a “serious risk” at the time
of approval or after approval if FDA becomes aware of
new safety information.

19. Reporting requirements
 A timetable of completion
 Periodic reports on the status of the study, including
whether any difficulties in completing the study
 Periodic report on the status of the clinical trial

20. Reporting requirements
• NDA—Field alert report
• distributed drug products
• articles to the FDA district office (within 3 working days of
receipt by the applicant)
• report and its mailing cover should be plainly marked:
“NDA—Field Alert Report.”
• any incident
• bacteriological contamination

21. Post approval labeling change
• 1.Current Level of Reviewed CBE-0 Supplements for
Safety-Related Labeling Changes Submitted by NDA
Holders
• 2.Current Level of CBE-0 Supplements for Safety-Related
Labeling Changes for Drugs
• 3.Current Level of CBER - reviewed CBE-0 Supplements
for Safety-Related Labeling Changes Submitted by NDA
Holders
• 4.Current Level of CBE-0 Supplements for Safety-Related
Labeling Changes Submitted by BLA Holders
• 5.Current Level of PAS Submissions for Changes to the
Highlights of Drug Labeling

22. Lifecycle Management
• The process of managing the entire lifecycle of a product
from its conception, through design and manufacture, to
service and disposal.
• It integrates people, data, processes and business
systems and provides a product information backbone for
companies and their extended enterprises.
• PLM describes the engineering aspect of a product from
managing description and properties of a product through
its development and useful life.

23. Benefits of PLM
1. Reduced time to market
2. Improved product quality
3. Reduced prototyping costs
4. More accurate and timely request for Quote generation
5. Ability to quickly identify potential sales opportunities and
revenue contributions
6. Savings through the reuse of original data
7. A framework for product optimization

24. Phases of PLM
1.Conceive
* Imagine, specify, plan, innovate
2.Design
* Describe, define, development, test, analyze and validate
3.Realize
* Manafacture, make, build, procure, produce, sell and
deliver
4.Service
* Use, operate, maintain, support, sustain, phase-out, retire,
recycle and disposal

25. FDA Inspection and Enforcement
 You should always be prepared for an audit!
 If you only prepare things just prior to an audit, it is very
apparent
 fresh paint over poorly prepared material
 all documents just signed or signed very recently very
apparent that hurried work was performed
 Last minute general cleaning and organizing is expected

26. Preparing for the Audit
• Most inspections are not announced
• General GMP inspections are performed approximately every
two years
• Pre-Approval Inspections (PAIs) are performed following
submission of filings with the FDA ANDA & NDA
• For Cause Inspections performed following an issue
• recall
• complaints

27. • Make sure any prior observations from auditors are
completed
• Were they completed on time?
• Were they effective in resolving the problem?
• If there were any issues, make sure they were explained.
• If things are not done, make sure you have a good excuse!!!
• What have you done in the interim???

28. The Close Out Meeting
• Decide in advance on response strategy
• Go through each item
• If errors are present, comment
• Corrections made during the inspection
• Corrected and verified Corrected and not verified Correction
promised by
• No comment
• Commit to a written response within a given time period

29. Re-establish Credibility
• Develop a corrective action plan (CAP) around the entire
scope
• Secure required resources
• financial and personnel
• Assign responsibilities and accountability
• Do not make commitments that can not be honored.
• Notify FDA of any set backs or missed timelines

30. Root Cause of the 483
• With the FDA’s new systemic approach the FDA wants a
systemic review of all your systems
• don’t just “fix” the issue, determine the root cause, evaluate
the solution and implement corrective actions
• evaluate across the board
• are there other systems with the same or similar problems

31. Establishment Inspection Report
• (FDA Form 482) inspection prior to the start of the actual
audit, signed by the highest authority.
• recording the minutes of all meetings with the FDA
inspector. Prior to the inspection, an internal audit of the
data submitted supporting the application should be
conducted.

32. FDA INSPECTION CLASSIFICATION - (NAI, VAI,
OAI & EIR)
• NAI (No Action Indicated) –
No objectionable conditions or practices were found
during the inspection
• VAI (Voluntary Action Indicated) -Objectionable
conditions are found but the District is not prepared to
take or recommend any administrative or regulatory
action
• OAI (Official Action Indicated) – Regulatory and/or
administrative sanctions will be recommended

33. • The company which receives a 483 should respond to the
FDA addressing each item within 15 working days.
• Good response can help the company avoid receiving a
warning letter, or stronger enforcement actions.
• FDA provides initial classification of the inspection based
on the observations noted during the inspection, the
investigator’s report, and FDA District Office supervisory
personnel review.

34. Warning Letter
The regulatory bodies – FDA and European Medicine
Agency (EMA) require pharmaceutical companies to comply
with cGMP standards. If FDA investigators observe any
violation these will be put down on a FDA 483 form. If these
GMP violations are regarded as critical or the response
letter was unsatisfactory, FDA may take an formal step by
sending a warning letter to the manufacturer.

35. Corrective Measures
• Upon receipt of the 483, FDA wants you to take instant and
adequate measures to correct the violations.
• All warning letters should be taken seriously, some of them can
potentially have more dangerous consequences than others.
• For example, if FDA warns you of a misleading advertisement
violating the regulations, you can more easily resolve the issue by
stopping that advertisement.

36. Recalls
• A drug recall is the most effective way to protect the public
from a defective or potentially harmful product.
• A recall is a voluntary action taken by a company at any
time to remove a defective drug product from the market.

37. Recall Classification
• Class I: A dangerous or defective product that could
cause serious health problems or death.
• Class II: A product that might cause a temporary health
problem, or pose slight threat of a serious nature.
• Class III: A products that is unlikely to cause any adverse
health reaction, but that violates FDA labeling or
manufacturing laws.

38. Weekly Enforcement Report
All recalls are posted weekly in the FDA enforcement report.
Recalls that are classified will have a classification of Class
I, Class II or Class III based on the level of hazard.

39. Determining the Effectiveness of the Recall
FDA evaluates the effectiveness of a recall by evaluating a
company’s efforts to properly notify customers and remove
the defective product from the market

40. Seizure
• Section 304 FDCA authorizes seizure of any food that is
adulterated or misbranded when introduced into
interstate commerce or while held for shipment in
interstate commerce
• Action is against the product itself, not against company
or employees
–Subject matter jurisdiction
• Seized product destroyed after finding of adulteration or
misbranding by court if not corrected

41. Seizure Process
• Magistrate issues "Arrest Warrant" for goods
• US Marshalls takes actual possessions or places good
"under seal" wherever he/she finds them
• Company must file "claim of ownership" w/n 10 days
• Matter handled as "civil action" with or w/o jury
• Notice of seizure must be published

42. Injunctions
• Used in situations which require immediate action to
safeguard welfare of consumers
• FDA may request preliminary injunction or temporary
restraining order
• temporary restraining order is fastest way to remove
product from the market
• preliminary injunction requires a hearing

43. Injunctions
• The purpose of this section is to provide instructions and
define responsibilities for those ORA units involved in the
development, preparation, processing, and follow-up of
injunctions.

44. Injunctions
• Consent Decree
–Opportunity to avoid injunction trial
• deficiencies must be corrected
• violative products destroyed
• FDA paid for filing cost
• FDA may impose other requirements
–Violation of injunction or consent decree punished by
contempt of court finding

45. ISO Risk Management Standard
• Risk is present in everything we do.
• ISO 31000, the international standard on risk
management, defines it this way:
• the affect of uncertainty on your objectives.
• Risk can be a threat or an opportunity Anything that could
harm, prevent, delay or enhance your ability to achieve
your objectives = Risk

46. ISO 31000:2009 :
• An international standard that provides principles
and guidelines for effective risk management
• Not specific to any industry or sector
• Able to be applied to any kind of risk
• Able to be applied to any kind of organisation
• Intended to be tailored to meet the needs of the
organisation

47. What Does ISO 31000 Cover?
• A set of risk management terms and their definitions
• A set of principles for guiding and informing effective risk
management for an enterprise
• An outline and process for creating a risk
management framework
• An outline and process for creating a risk
management process

48. Why Use ISO 31000?
• Save yourself time and effort
• Facilitate communication
• Provide higher quality output

49. References
• 1. [Internet]. Fda.gov. 2018 [cited 10 December 2018]. Available
from:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegul
atoryInformation/Guidances/UCM404441.pdf
• 2. [Internet]. Fda.gov. 2018 [cited 10 December 2018]. Available
from:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegul
atoryInformation/Guidances/UCM217043.pdf
• 3. [Internet]. Fda.gov. 2018 [cited 10 December 2018]. Available
from:
https://www.fda.gov/downloads/Drugs/Guidances/UCM217043.pdf

50. • 4. Sarnikar S, Woosley R, Gupta A. An Information Technology
Architecture for Drug Effectiveness Reporting and Post-Marketing
Surveillance. SSRN Electronic Journal. 2007;.
• 5. Inspection, Compliance, Enforcement, and Criminal
Investigations [Internet]. Fda.gov. 2018 [cited 10 December 2018].
Available from: https://www.fda.gov/ICECI/
• 6. Warning Letters [Internet]. Fda.gov. 2018 [cited 10 December
2018]. Available from:
https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/de
fault.htm

51. • 7. Seizures and Injunctions - Health Fraud [Internet]. Fda.gov.
2018 [cited 10 December 2018]. Available from:
https://www.fda.gov/ForConsumers/ProtectYourself/HealthFraud/u
cm272203.htm'
• 8. Leitch M. ISO 31000:2009-The New International Standard on
Risk Management. Risk Analysis. 2010;30(6):887-892.