# Presentation: 697083

## Mastering Regulatory Compliance FDA Drug Educational Forum  Kansas City - May 11, 2005 

- Thomas J. Arista
- Investigator
- National Expert / Biotechnology
- Office of Regulatory Affairs
- Division of Field Investigation
- Dallas, Texas
- (214) 253-5282
- tarista@ora.fda.gov

## Mastering Regulatory Compliance

**A Question -**
- Who runs the shop?
- Who oversees the operations?
- Who has final authority and approval?

**Organization / Department ? **
- Production
- Validation
- Engineering
- Quality Control Unit
- Regulatory Affairs

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Let us consider your Shop - *Home town, USA*
*Small shop*
*Not to large shop*
*One of the big guys*

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Type of finished products e.g.,
- Sterile or non-sterile
- Solid oral dosage
- Liquids
- Large volume or small volume parenterals

- Type of manufacturing operations e.g.,
- Active pharmaceutical Ingredient, (API)
- Aseptic filling
- Isolator technology
- Mixing, Blending, Isolation, Purification

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Some of the manufacturing steps are:
- Critical steps ?
- Important steps ?
- Less important steps ?
- Required steps?

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Does your process use computer assisted automation?
- Fully - automated
- Semi - automated
- Non - automated

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- What are the Quality Control analytical test  requirements?
- In-process control checks
- Chemistry/Microbiology
- Finished product QC test requirements / specifications
- Stability Tests

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- How much information is needed?
- Type of info / data e.g.,
- Process Validation
- QC analysis
- Data to support manufacturing operations

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## FDA defines Process Validation

*Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre- determined specifications and quality characteristics.  *

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Process Validation

- Let’s put the legal jargon aside for a moment.
- I like simplicity. How about the following thought?

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Validation

- 	“*In today’s pharmaceutical industry, whether you are thinking about a computer system, a water treatment systems, or a manufacturing process, validation means nothing more that well-organized, well-documented common sense.”*
**Kenneth Chapman **
**Director Quality Assurance Pfizer, Inc.**** **
**A *****History of Validation in the United States***
**Pharmaceutical Technology, 10/91**

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- When you go back to your shop ask your staff, (e.g., operator/analyst), the following 2 questions and 1 request.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Question #1- ***What do you do?***
- 	Specifically, what needs to be executed to accomplish the manufacturing steps or QC analysis?

***Examples -***
- Weight out raw materials;
- Maintain proper operation of the Water System;
- Perform qualifications of production or laboratory equipment;
- Aseptic processing
- QC Analysis

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Question #2 – ***How do you do it?***
- 	Specifically, how do you perform the manufacturing steps or QC analyses that need to be accomplished?

***Examples –***
- Follow Standard Operating Procedures
- Written Protocols
- Pharmacopoeia methods
- National or International Standards, (e.g., AAMI, ISO)

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- Request #1-
***Show me.***

- That is:
***Show me*** what you do
***Show me*** how you do it
***Show me*** the data to support successful execution of the  manufacturing steps
***Show me*** the analytical data

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## What does the question do for you?

_*Question #1- *_
*	**What do you do?*
**	****For, the individual who did the work, (e.g., Operator, Analyst, Technician).**

- Individuals will describe their normal day-to-day operation.
- This also assist to demonstrate the individuals’  level of knowledge and comprehension of their respective jobs.
- Or, they may describe some inconsistencies with current established procedures.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## What does the question do for you?

_*Question #2 – *_
*How do you do the work?*
**	****For, the individual who did the work, (e.g., Operator, Analyst, Technician).**

- The written SOP describe the specific work required to be performed.
- The SOP is complete and accurate.
- The SOP may not be current and does not accurately describe the steps performed.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## What does the question do for you?

_*Question #2 cont. – *_
*	**How do you do the work?*
**	****For, the individual who did the work, (e.g., Operator, Analyst, Technician).**

- Individuals are executing the specified operations as described in established protocols.
- The manufacturing steps are successfully executed with the required specifications and acceptance criteria achieved.
- Individuals may be performing the requisite operations in an inconsistent manner as described in the protocols.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## What does the request do for you?

_*Request #1 –*_* *
*	**Show me.*
**	****For, the individual who did the work, (e.g., Operator, Analyst, Technician).**

- The data supports the manufacturing steps and  QC analysis.
- The data supports the successful execution of the defined specifications described in protocols.
- Or, the data documents manufacturing inconsistency, or does not support the requisite production steps and the QC analysis.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Some times...

- 	The SOPs are written just short of the preamble to the Constitution.

- FDA Drug Educational Forum - Kansas City

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## Some times...

*	**“**We the people of the great sovereign domain we call Production with our brothers and sisters from the far away, never, never land called Quality Control Laboratory promise to come together everyday, or as much as we dare to tolerate (which ever comes first), to do everything for everyone at all times so help us, us.” *

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Some times...

- The established procedures are not followed.
- The SOP is not complete or accurate.
- Specifications established in protocol acceptance criteria are not met.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## So then....

- Assure that the written procedures and protocols are complete and accurate;
- Assure that personnel are following all of the requisite manufacturing steps as described in the SOP or protocols;
- Assure that laboratory analyst are performing the appropriate methods of analysis, (e.g., pharmacopeias  compendia).

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Some times...we drop the ball

- How do we correct the issues or concerns?
- In response to the issues or concerns, were the corrective actions appropriate?
- Are concerns or deviations addressed within a reasonable period of time?

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## Changes

- There may be changes, (e.g., adjustments, refinements), to the manufacturing operation.
- Minor
- Major

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## In the event of changes...

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## In the event of changes...

- Are the changes major or minor?
- How do you determine if the changes are major or minor?

- Who do you ask?
- There are knowledgeable individuals who can determine if changes are major or minor.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## In the event of changes...

- Do the changes impact upon the finished product or manufacturing process?
- How do you determine the impact of changes?

- There are knowledgeable individuals who can determine if major or minor change impact the finished product or manufacturing process.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## In the event of changes...

- The individual changes, when considered collectively, do they present a departure from the validated process or equipment qualifications?

- Who do you ask?
- There are knowledgeable individuals who can determine if the  changes, collectively, do not impact upon the validated process or equipment qualifications.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## In the event of changes...

- Do the changes require a Supplement to be sent into the Center?
- Or, can the changes be included in an annual product review?

- Who do you ask?
- There are knowledgeable individuals who can determine if a supplement is required.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Changes require assessment

- Who do we ask in order to answer the questions?

- The knowledgeable individuals;
- Production
- Validation
- Engineering
- Quality Control Unit
- Regulatory Affairs

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Changes require assessment

- The knowledgeable individuals may employ a variety of evaluation tools to determine impact of the changes and if there are operational or regulatory risks.

- For example:
- Faulty Tree Analysis, (FTA)
- Failure mode and effect analysis, (FEMA)
- Hazard Analysis Critical Control Points, (HACCP)

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Changes require assessment

- What if there is no formal evaluation tools, (i.e., the examples in the preceding slide)?

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Not to worry...

- Your currently performing;
- Evaluations
- Assessments
- Determining the impact and/or risks
- Providing recommendations

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Not to worry...remember..

- What you do, how you do it, and the supporting data is in a *Change Control* documents, SOP or protocol.

- The document describes and answers many questions concerning the ***evaluation process*** and ***rationale*** to support the major or minor changes and there impact upon the manufacturing process.

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

**A Question -**
- Who runs the shop?
- Who oversees the operations?
- Who has final authority and approval?

**Organization / Department ? **
- Production
- Validation
- Engineering
- Quality Control Unit
- Regulatory Affairs

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- The Code of** **Federal Regulations (CFR) describe a number of responsibilities requirements, and oversight activities of...

- The Quality Control, (QC), Unit

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Mastering Regulatory Compliance

- A successful QC Unit obtains assistance, knowledge, and support from:
- Senior Management
- Production
- Validation
- Engineering
- Quality Control laboratory
- Regulatory Affairs

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Recommendations for NDA/ANDAs September 2003 – April 2004

- Inadequate QA Functions 2%
- Inadequate SOP 2%
- Facility withdrawn – 3%
- Previous Deviations persists  7%
- Inadequate Lab controls 7%

- Drug not made at site 8%
- Contamination 13%
- Others 15%
- Pending Regulatory Action 18%
- Firm Not Ready 25%

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## FDA Internet addresses

- Human Drugs:
- http://www.fda.gov/cder
- Biologics:
- http://www.fda.gov/cber
- Devices:
- http://www.fda.gov/cdrh
- Vet Drugs:
- http://www.fda.gov/cvm

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

## Coming up next...

- Financial Incentives for Small Businesses
- Ron Wilson, Director, CDER Small Business Assistance

- FDA Drug Educational Forum - Kansas City

- May 11, 2005

**Notes:**
RONALD L. WILSON is the Director of Small Business Assistance in the Office of Training and Communication (OTCOM), Center for Drug Evaluation and Research (CDER). Small Business Assistance is a new function within CDER providing assistance to small pharmaceutical businesses especially with new drug development. He formerly was Director of the Health Assessment Policy Staff in the Office of the Commissioner where he was responsible for several functions, which included the patent term restoration program and the agency’s institutional review board educational program. Before coming to the Office of the Commissioner, Mr. Wilson was the Chief of the Administrative Compliance Branch in CDER where he directed the final phase of the Drug Efficacy Study Implementation program. He has been the recipient of several commendable service awards and was selected for FDA’s Leadership Development Program. Mr. Wilson is a registered pharmacist with a masters degree in public administration.