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Imagine a Pharmaceutical Manufacturing System as a Three dimensional figure, and a regulatory audit as a cross sectional sample of this three- dimensional figure.. a Each person engaged

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PHARMACEUTICAL SAMPLER

All Rights Reserved.

Copyright 2012 by Dave Cortes

Cover Art 2012 Dave Cortes

Cartoons 2012 Dave Cortes

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or retrieval system, without the prior written

permission of the editor

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INTRODUCTION 5

1 WHY THIS BOOK IS DIFFERENT? 5

2 HOW THIS BOOK IS ORGANIZED 12

OBSERVATION #1: TRAINING 15

STATED OBSERVATION: 15

CODE COMMENTS 16

EDITOR COMMENTS: 17

OBSERVATION #2: FACILITES AND EQUIPMENT 19

STATED OBSERVATION: 19

CODE COMMENTS 20

EDITOR COMMENTS: 21

TIPS FOR JUSTIFICATIONS: 22

OBSERVATION #3: QUALITY SYSTEMS 23

STATED OBSERVATION: 23

CODE COMMENTS 24

EDITOR COMMENTS: 25

TIPS FOR JUSTIFICATIONS: 26

OBSERVATION #4: PRODUCTION SYSTEMS 27

STATED OBSERVATION: 27

CODE COMMENTS 28

EDITOR COMMENTS: 28

OBSERVATION #5: CLEANING VALIDATIONS 30

STATED OBSERVATION: 30

CODE COMMENTS 33

EDITOR COMMENTS: 34

1 WHY THIS BOOK IS DIFFERENT?

If today an FDA auditor comes to your

operation site, there is a 54.1% that you will

receive a dreaded 483-form full of non compliance observations.

On 2010 the FDA issued 646 483’s to the pharmaceutical plants they visited The question then becomes how to prepare or mitigate the probability of receiving a 483 observation?

We believe that the best way to prepare for this occurrence is to gain experience from past examples of 483’s observations and use them as Business Cases Studies.

Case studies illustrate psychological principles and Technical knowledge in a way that abstract generalizations and statistics cannot In addition they construct a more detailed

depiction of a problem and its boundaries better than any other method.

Until now the Drug Manufacturing industry has relied on a descriptive process to assess its Regulatory Vulnerability Specifically, the preferred way to evaluate the vulnerability of the drug manufacturing systems is by performing Audits, Assessment and Evaluations These processes are done by “experts” that evaluate the different manufacturing systems and express an opinion on the individual system

in question After a typical one or two week assessment, the “expert” auditors produce an assessment report with a summary of good practices and gap finding Given that there is a

54.1% chance of a pharmaceutical operation to

receive a 483 Form, it seems this approach has

a pretty bad performance record But why would the Auditors predict so badly? Can it be improved?

Behavioral Meta studies have shown that

“expert judgments” are no more accurate than

those of lightly trained novices and are less accurate that actuarial mathematical models.1

This is a troublesome fact that seems to be a dirty little secret of quality departments But let’s reflect on this methodology for a moment, using a physical metaphor Imagine a Pharmaceutical Manufacturing System as a Three dimensional figure, and a regulatory audit as a cross sectional sample of this three- dimensional figure

1 Camerer and Johnson, (1993), “The process-performance paradox in expert judgment”

The prior figure illustrates the concept, and shows two dimensional cross section samples (A,B, and C), taken from the three dimensional figure

As it can be seen in the figure, these cross sectional samples can give a good

understanding of the complete figures, but

only on the chosen path of the cross section

Note that they cannot explain the true nature

of the three dimensional contour of the figures,

as this will require the sum of an infinite

number of cross sections to have a full understanding of the three dimensional figure.

In the same way, due to practical constraints,

a regulatory audit seeks to provide only reasonable assurance that the systems are free from material error, not the true status of the vulnerability of the system

This is a huge realization, as the TRILLION DOLLARS Pharmaceutical industry relies completely on a process that could only glimpse the true nature of the vulnerability

of its systems.

Empirically, this is the reason why many concurrent regulatory assessments diverge significantly from each other; they depend on limited cross sectional samples of the dynamical system Compounding this fact is that, by design, the audits are path dependant exercises with completely random initial variables like auditor preference and expertise, current customer complaints or documentation samples

For example, a corporate auditor that knows

or likes laboratory systems will focus on them,

but will not choose to focus, or know how to focus, on the interdependency of the facility or the equipment.

Another empirical example is that, it is typical to have corporate assessors produce similar audit results year after year, and then receiving an FDA assessment that diverges completely from the corporate assessment This occurrence could give the perception of a lack of rigor from corporate assessments, but in reality is the systemic futility of attempting to define a three dimensional system by randomly selecting cross sections of the system The insight of this introspection is that this is not the result of audit weakness, is more profound,

it is a systemic flaw of the only tool available

to diagnose Regulatory Vulnerability.

We can go even farther and state that a descriptive vulnerability Audit can do more harm than good, as they provide a false sense

of security with the illusion of understanding the non-linear relationships of a dynamical system.

That is the reason for this compilation The Training professional has to become the auditor, as it is the only expert that can really identify the many systemic interdependencies

of their own systems You are the only one that can take the time to make the infinite cross section analysis of the contour of your systems to ensure full regulatory compliance.

We have compiled 5 different 483 observations that will help you answer, what the FDA is watching and what is typical observation related to Training Management The Pharmaceutical Professional can use these Case Studies as a mirror where they can look for weakness in their own operations and strategically choose to preemptive attack those vulnerabilities.

These Case Studies can teach your team first TO-SEE its own vulnerabilities, then help them train on how to solve them, and finally give Regulatory power to the capital appropriation justification of these projects.

Dave Cortes, PE

March 2012

2 HOW THIS BOOK IS ORGANIZED

This book is divided into 20 different observations from many different 483 Forms Some observations are part of the same 483 Form, others are not The reason to state many observations from the same Form is that

it is typical for an FDA inspector to quote different non compliance findings from the same root cause

When a systemic weakness is found, there could be innumerous regulations non- compliances; our approach makes it easier to understand the different Regulatory risk from a single finding

In addition, each Observation is divided into 6 Parts:

1 Heading – This Parts Includes, the date

the Form was issued, the name of the addressed Company, the FDA Regional Office that gave the Form, and finally the observation number, an important fact, given that usually the Findings are detailed in descending importance

2 Stated Observation- A verbatim quote

of the Observation from the selected 483 Form

3 Code Comments – A quote from the

applicable CFR from the FDA Code.

4 Editor Comments – Professional Opinions and pointers on the scope and impact

of the observation.

5 Auditors Names – The name of the

auditors as identified in the 483 Form.

FDA’s 483 SUMMARIES

*****************************

OBSERVATION #1: TRAINING

or is represented to possess.

Specifically, the individual responsible for providing training to the Microbiological Laboratory personnel is a Chemist with limited background in Microbiology.

CODE COMMENTS

Federal code Title 21 Part 211, “CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS” is the Regulation that states the requisites for Pharmaceutical manufacturing Specifically, Sec 211.25- “Personnel qualifications”

is the core of the regulation related to Training

On this Observation let’s refer to Sec 211.25 Personnel qualifications

(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person

to perform the assigned functions Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations)

as they relate to the employee's functions Training in current good manufacturing practice shall be conducted by qualified

individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.

(b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess

(c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product

EDITOR COMMENTS:

Corporate budget constraints sometimes run into with the Regulation Many times management has the presumption that personnel can assume additional responsibilities given their technical

background, without considering the specific educational knowledge of the responsibility.

The expectation of the Regulators is to have a technical background and experience on the specific area of responsibility In the eventuality that budget constraint precludes the hiring of a technical match, efforts have to be made to train or certify the personnel in the specific area of responsibility This is not as hard as it looks For example, Microbiology College classes or even Microbiology Professional e-training could have help justify the regulator that the personal had a basic knowhow that in addition to the related method experience qualified the person for the given job

INVESTIGATORS

Marie A Fadden,Joel D Hustedt, Sandra A Hughes,Justin A Boyd

OBSERVATION #2: FACILITES AND EQUIPMENT

COMPANY

CARACO PHARMACEUTICAL LABORATORIES

OFFICE LOCATION: Detroit

Specifically, Raw material warehouse facility (b)(4) did not have adequate storage available for all of its raw materials and in-process (b)(4) materials For example:

(b)(4) Digoxin lot was in location "FRSH (Fresh) without a specific location designated for the warehouse from 10/13/08 to 1/26/09

B (b)(4) Digoxin lot was in location "FRSH" (Fresh) without a specific location designated for the warehouse from 12/30/08 until it was reported missing

C (b)(4) Digoxin lot was in location "FRSH (Fresh) without a specific location designation for the warehouse from 9/15/08 to 9/26/08

D Baclofen, USP (b)(4) lot (b)(4) was in location

"DISP" (Dispensing) without a specific location designated for the warehouse from 4/22/08 through 7/25/08

E Metoprolol Tartrate, USP Iot (b)(4) in location

"DISP" (Dispensing) without a specific location designated for the warehouse from 5/15/08 through 9/25/08

CODE COMMENTS

The Subpart C—“Buildings and Facilities” in Sec 211.42- “Design and construction features” states that:

(a) Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations

(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mixups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination The flow of components, drug product containers, closures, labeling, in- process materials, and drug products through the building or buildings shall be designed to prevent contamination.

(c) Operations shall be performed within specifically defined areas of adequate size There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course

of the following procedures:

EDITOR COMMENTS:

The fundamental responsibility of the facilities and equipment professional is to offer an adequate facility for pharmaceutical manufacture The risk assessment and risk mitigation of a possible space constraint cannot be delegated to the quality personnel; it must be identified by the facilities and equipment team