Process Validation Module - WordPress.com€¦ · Process Validation Module Challenge: Miss Wormwood fell and broke her hip and has to have surgery. Due to her age, cigarette smoking

Process Validation Module

Challenge: Miss Wormwood fell and broke her hip and has to have surgery. Due to her age, cigarette smoking

habit, being overweight, and having been bed-ridden since the fall that caused the break, she is at risk for a

pulmonary embolism. Although Calvin may present the attitude that he does not care about the course material, he

now sees a legitimate reason why what he has learned in his class is so important. The hospital plans to give Miss

Wormwood a recombinant therapeutic protein to prevent a pulmonary embolism. Calvin wants to do his best to

understand how the pharmaceutical company that produces the protein (that also retained his father as a patent

attorney) insures that the protein is not only effective but safe for her to take.

Generate Ideas: In class, have students make journal entries to answer the following five questions: (1) what are

your initial ideas about how recombinant therapeutic proteins are produced? (2) What are the critical process

parameters in each process step? If you don‟t know, how would you determine what they are? (3) For each

process step, how many and what types of measurements would you make to ensure that the process design is

consistent? (4) How would you document this? (5) Who would need to approve your methods and why?

Multiple Perspectives: In the whole-class setting, have the students share ideas from their journals. Formatively

evaluate these to assess if students see the need for a clear understanding of (1) the protein production process, (2)

the critical process parameters associated with each step of the process, and (3) the need to measure, validate and

document each process step to insure reproducibility, safety and efficacy.

Next, read the expert interview of Dr. William Hall that will guide the students to see the need for a process

validation program. Work with students in a discussion format to create a plan of action and required knowledge.

Process Validation Module

Multiple Perspectives

An Interview with Dr. William E. Hall, Hall & Pharmaceutical Associates, Inc.

1. If I have an infection and am given an antibiotic, how do I know that the dose is the same?

If the company manufacturing the product is a reputable manufacturer, then they have to prove that the dose

is the same in each and every dose. Now of course they are allowed some variation to account for variation

due to manufacturing and analytical variation. After all, the products were made by humans so there is some

slight variation, but usually not more than + or – 10% for an antibiotic, even less for a non-antibiotic

product. The test that the company that manufactured the product must run is known as a „content

uniformity‟ test, which is pretty self-explanatory (i.e. content uniformity is the test to see if the dose is the

same or uniform from one tablet to the next. During the development phase of the product the company tests

many thousands of tablets to gather the data that proves that the product will deliver a uniform dose

consistently from one dose to the next. (If I should happen to meet you in person ask me about a situation in

Australia when the company made a product that did not have good content uniformity.)

2. Who is responsible for determining that each dose is the same?

The responsibility for determining that the dose will be uniform or the same is a shared responsibility. The

pharmacists in the research and development department (usually known as R and D) are responsible for

finding out how to make the product uniform during the development stage. They determine such critical

factors as how much mixing is required to uniformly distribute the active ingredient throughout the other

ingredients in the product (known as excipients) that will be compressed into tablets to make the product.

After the product is developed and marketed, then the responsibility for making sure that the dose is the

same today, tomorrow, and forever falls to the Quality Department of the company. This department is

divided into Quality Assurance, who makes sure that the production department carries out the procedure

the same way for every batch by auditing them daily and the Quality Control section which pulls samples

from the production batch and tests them.

3. How do they do it? With what accuracy can they do it? With what accuracy MUST they do it and

why? When do they do it and why? Do they have to record any data? If so, what?

That is a very good question and it will be difficult to give a short answer. The test for antibiotic potency is

done by a method called “zone of inhibition”. This test involves dissolving one tablet into sterile water and

then placing one drop of that solution on a petri dish which is filled with media, which is like a food for

bacteria. The plates are set aside in a nice warm, cozy area and the bacteria are allowed to grow for a certain

period of time (sort of like snacking while watching pro football on Sunday afternoon). The bacteria grow

real fast in the places not close to the drop of antibiotic, but the antibiotic keeps them from growing up close

to the drop. The result is that the drop has a clear area around the drop where no bacteria could grow. The

larger this circle of „no growth‟ the more potent the antibiotic. So by measuring this “zone of inhibition”, the

lab scientist can calculate just how potent the tablet was. The test is run many times and the average result is

calculated.

The accuracy of the test must be at least + or – 5% if not better. The allowable accuracy is determined by a

combination of the accuracy of the test and the variability in the technique of the laboratory person

performing the test. This is one of the reasons that the lawyers attack the lab results in court (think CSI)

because if they can show that the lab scientist did not use proper technique, they can invalidate the results

and their client can be exonerated of the charges against him or her.

The tests on all products must be done before the product is released and allowed to be sold. Thus, the proof

of quality must be determined by testing before the product can even be moved from the quarantined area

and onto the trucks for shipment.

The test data must be reviewed by a laboratory supervisor as a part of the final product release process for

each individual product batch. The data is also reviewed by the FDA (Food and Drug Administration)

inspectors when they perform inspections of every manufacturing facility every two years. So there are

many checks of the data and the laboratory must comply with every aspect of the regulations as specified in

great detail in the current Good Manufacturing Practices (cGMP) Regulations as well as the current Good

Laboratory Practices (cGLP) Regulations. These are regulations, i.e. they are not optional.

4. Does someone check behind them to make sure they are not making a mistake? Who and how? Does

their criteria for checking change? Why and how often? What drives change?

I actually answered the first parts of your question in the previous answer. However, the last part of your

question is very interesting and also very good. The best part to answer first is the last part of your question,

i.e. “what drives change?” Change is driven by changes in drug therapy (the acceptable dosage for certain

drugs, especially new drugs sometimes changes as well develop more experience with treatment of different

medical conditions. Changes also occur due to the technology. As you know, the laboratory scientists are

always developing new and better methods of assaying products and this results in changes in the way that

we test the products. Techniques are available today that were not available as recently as 5 years ago. For

example, today‟s analytical methods are able to detect drugs with a sensitivity of 1 part per billion (ppb),

that is 1 part in 1,000,000,000 and less. That is totally awesome! We are using these powerful tools to learn

constantly about our drugs.

Another driving force for change is the improvement in how drugs are administered to the patient resulting

in more of the drug getting to the place in the body where it is actually needed. For example, if you have an

infection in your foot and you take an antibiotic tablet, you might be surprised to know that only a small

fraction of what you took actually reaches your infected foot. This concept, known as bioavailability, is very

important. For instance, say you take 500 mg of an antibiotic. Maybe a few years ago, only 100 mg of that

500 was actually absorbed into your body. The other 400 mg was excreted in the feces or urine and never

did you any good at all. The pharmaceuticals scientists have found ways to administer drugs in the last few

years that give a greater percentage of bioavailability. Thus instead of giving you a 500 mg tablet, they can

give you a 100 mg tablet. This is the case where less is actually more. Why? Because along with every drug

comes side effects – these are the bad things that can happen to you when you take the drug, such things as

extreme nausea, diarrhea, and vomiting. You don‟t want to go there- right? Well, one good thing about

decreasing the dose of most drugs is that by doing so you also decrease the undesirable side effects. Perhaps

you‟ve heard about people who have cancer and have terrible attacks of nausea. Well, the last few years

they have found ways to give the drugs for cancer than increase the bioavailability, thus decrease the side

effects such as nausea. The patient may also be less likely to lose their hair with certain anti-cancer drugs.

So we are making some progress.

5. Do they check periodically to make sure that what they said they could do they could indeed do? How

frequently?

All reputable drug companies are constantly evaluating their products. They do this by a variety of methods.

First, they actually go to the companies that make the ingredients for their products and inspect them. They

know that their products can be of no better quality than their starting materials. “Garbage in – garbage out”

is not just a computer cliché.

They also must keep a retained sample of every batch of product released to the market. If they get a

complaint from a patient or from a doctor that the product did not physically look as it should (and patients

know what their medicine should look like) or if the drug does not give the desired or expected effect, then

the company wants to know about it and they will then test the retained sample of the specific batch to see if

it is still full potent. This „feedback‟ from real people is very important to tracking the performance of the

product.

6. What are the characteristics of a pharmaceutical product that are important to its safety and

efficacy? How are they determined? Are they the same for every product?

There are many measurable characteristics of a pharmaceutical product that contribute to safety and

efficacy. The new drug must be evaluated for any factors could affect its safety and efficacy – such things

as mutagenic, teratogenic, carcinogenic effects as well as toxicity and potency. The drug may be unsuitable

for pregnant patients or even females of childbearing age. There may also be medical conditions for which

the new drug cannot be used, referred to as contraindications. Each of these must be evaluated for every new

product and this „proof‟ must be submitted to the FDA as part of the New Drug Application (NDA). The

first studies are performed on animals to establish how the body metabolizes and excretes the drug and how

toxic the drug is in animals. The most important of these factors is the data gathered during the clinical trials

of the drug during the development phase long before the product reaches the general market. The clinical

trial is actually composed of 3 distinct phases. During phase 1 of the clinical trials, the new drug is tested in

animals in very small, sub therapeutic doses to determine how the body. During phase 2 of the clinical trials,

the drug is administered in small doses to a few human patients in good physical condition, i.e. those not

having any serious medical condition including the medical condition for which the drug will be used. The

purpose of this study is to determine how the drug is metabolized and excreted in humans, how toxic the

drug may be, determine any side effects or contraindications, and get a general idea of what the therapeutic

dose of the drug will be. During phase 3 of clinical trials, the new drug is tested at full therapeutic dose in a

large number of patients.

7. Is everything measured? Does someone say what is important and what is not? Based on what?

Patients are fully characterized during the clinical trials. They are fully evaluated as to physical properties

such as age, weight, and any pre-existing medical conditions are fully documented. The patients are

monitored and measured throughout the study. Placebo doses are administered to determine if the medical

effects are real or imagined.

The most important evaluation of the clinical trial data is that performed by medical personnel that serve as

advisor panels to the FDA. They are subject matter experts (SMEs) who advise the FDA on whether the

drug should be approved or not. They essentially say what is important and what is not and, most

importantly, they answer the question “Does the benefit of having the drug available on the market

outweigh the negative side of adverse drug reactions?” Sometimes it‟s a tough decision.

8. Does how much the manufacturer makes matter? How is it determined how long the product can

last? What does the product expiration date really mean?

The size of the batch does not influence the stability and thus the shelf life of the individual tablets. A given

product will have the same expiration date regardless of whether it is made in a large batch or a small batch

size. However, if a drug is very unstable, then it may be made in another form e.g. a freeze dried powder

which can be reconstituted at the time of use or it might be required to be stored in a cool place to prolong

the activity of the drug.

How long a drug can last depends on the intrinsic stability of the drug in the dosage form and it must again

be experimentally determined. Usually, a drug product is considered no longer fully potent when the

concentration of active ingredient or the amount of active ingredient has decreased to 90 % of its labeled

potency. Thus, if you had an antibiotic product that normal had 500 mg of active ingredient, then if it took 2

years or 24 months for the amount of active to decrease to 450 mg, then the expiration date would be 24

months from the date of manufacture. This expiration date is established by storing the drug in a

temperature controlled cabinet and periodically testing the product, i.e. the expiration date is determined by

real time testing of the product under different conditions of temperature and humidity.

It is important to note that the expiration date and the storage conditions specified on the label are tied

closely together. If the product is labeled with an expiration date of October 2011 and the label specifies

store in a controlled room temperature, and for some reason you leave it on the window sill in your kitchen

where the afternoon sun beats down on it and the temperature reaches over 100 degrees, then the product

will likely not be fully potent until October 2011, i.e. it will go bad before then.

Respectively submitted,

Bill Hall

Research and Revise:

Topic One – Learn/review the protein production process

Review Scientific American & Trends in Biotechnology articles on recombinant proteins. Discuss articles in

class.

Velander, William H., Lubon, Henryk; Transgenic livestock as drug factories. Scientific American, Jan97, Vol.

276, Issue 1

Michael K. Dyck, Dan Lacroix, Franc¸ois Pothier and Marc-Andre´ Sirard. “Making recombinant proteins in

animals – different systems, different applications” TRENDS in Biotechnology Vol.21 No.9 September 2003

Play “Manny the Biotech Goat” board game as review of upstream and downstream bioprocessing.

Manny the Biotech Goat

Developed by Hector Lopez Pelet Validation Contractor

East Carolina University alum

| Instructional Objective | Learners & Context | Object of Game | Game Materials |

| Time Required | Rules | Design Process | References |

Instructional Objective

To present in an interesting way, the process for the manufacture of Antithrombin (ATryn) with emphasis in the Bioseparation techniques involved.

To use the game as an interactive learning experience.

Learners & Context of Use

This game is designed for Biotechnology students of undergraduate level. The game is intended to be played in the classroom as an interactive learning experience for a biotechnology separations techniques course. The game could be used as part of a final course grading tool, to demonstrate student’s proficiency in the subject matter: Principles of Bioseparation Techniques.

Object of the Game

The object of the game is to be the first to reach the end. If played in the classroom as a grading tool, each group of 4 students will compete for the following prices:

1st player to get to the finish gets 10 points for the final exam, or 5 points towards the final course grade.

2nd player to get to the finish gets 8 points for the final exam, or 4 points towards the final course grade.

3rd player to get to the finish gets 6 points for the final exam, or 3 points towards the final course grade.

4th player to get to the finish gets 4 points for the final exam, or 2 points towards the final course grade.

Game Materials

The game is comprised of the following components:

The board game

Player indicator/markers (4 colors)

A dice

Game cards (Question and Answers) colored by specific game sections.

Time Required

Time required for game set-up should not exceed 10 minutes due to the simplicity of design. Game plating should take from 30 minutes to 1 hour for 4 players.

The Rules

The rules for the game are as follows:

1. Each player will select a player marker.

2. Each player will roll the dice to select starting positions. The highest dice value will start first, the second highest will start second, etc.

3. The first area to play will be the yellow path.

4. The first player will select a card from the yellow pack.

5. If correctly answered, the player may roll the dice to advance.

6. If incorrectly answered, player stays at the current step.

7. Afterwards, the next player will repeat.

8. If a player lands in a square with this symbol the player will lose his/her turn to answer a card question.

9. If a player lands in a square with this symbol the player will go back one step.

10. If a player lands in a square with this symbol the player will advance one step and will have the option of selecting a mystery card.

11. The yellow path will contain questions referent to general Bioseparation techniques and issues particular to the process of the creation and generation of transgenic goats for the production of therapeutic protein, in this case Antithrombin III or Atryn.

12. The red path will contain questions referent to general Bioseparation techniques and issues particular to the processing of the milk obtained

from transgenic goats to produce therapeutic protein, in this case Antithrombin III or Atryn.

13. Mystery questions, if correctly answered, can give player extra steps. No penalty for incorrect answers.

14. First player to reach the Start point wins.

Design Process

The design process was based on examples given from past educational board game projects and the reference information obtained, from the course textbook and subject matter articles.

References

The references used for this game where from the course textbook, Journal Articles, and educational board game project examples.

Books & Journals Ghosh, Raja (2006). Principles of bioseparations engineering. Hackensack, NJ: World Scientific.

Electronic

http://edweb.sdsu.edu/Courses/EDTEC670/boardgame/board-game-template.html http://www.printgames.net/english/printgames_e.htm http://eprentice.sdsu.edu/F03670/giveandtake/ http://www.fda.gov/cber/gdlns/bioplant.pdf http://www.fda.gov/CBER/label/atrynLB.pdf http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4410B1-4.pdf http://agribiotech.info/AlisonGE%20Animalssent%20to%20web%2002.pdf

Red Section – Milk extraction from transgenic goats thru final ATryn process, plus general

Bioseparation questions:

Cut along the dotted lines and fold in the middle.

Fat is removed from the milk from transgenic goats for ATryn manufacture by

means of _______.

Answer: Centrifugation

Mention one general type of centrifuges.

Answer: Sedimenting / Filtering

Mention one category of centrifuges.

Answer: Laboratory / Preparative

What is RCF? Answer: Relative Centrifugal

Force

Casein is removed from the milk from transgenic goats for ATryn manufacture by

means of _______.

Answer: Membrane Filtration

Extraction depends on the _________________ behavior of the solute

between phases.

Answer: partition

The objectives of downstream process are to

_______ the number of steps and ______ the yield

for each step.

Answer: minimize, maximize.

The most used chromatography technique

for the separation and purification of proteins is

____

Answer: Ion Exchange

Extraction is the ___ of solute from one fluid to

another Answer: transfer

Adsorption is the _________ on solid

material surface. Answer: molecular binding

Mention one Chromatography mode of

operation. Answer: Pulse / Step

______ is separation based on migration in an

electromagnetic field. Answer: Electrophoresis

Hydrophilic means that the medium _______ water

Answer: likes

Mention one type of filtration used during the downstream process of

ATryn?

Answer: Nanofiltration, Anion Exchange Chromatography

What type of filtration is used during the

downstream process of ATryn as a viral removal

step?

Answer: Nanofiltration

Mention one of the most widely used filtration

membranes in protein purification.

Answer: Microfiltration / Ultrafiltration

What is HIC? Answer: Hydrophobic

Interaction Chromatography

The final ATryn product is __________ and then heat

sterilized.

Answer: Lyophilized / Freeze dried.

Lyophilization is a process in which _____ is removed

from a product after it is frozen and placed under a

vacuum to generate a sublimation state.

Answer: water

At what temperature is ATryn heat sterilized?

Answer: 80°C

Yellow Section – Goats Genetic Manipulations, plus general Bioseparation questions:

Cut along the dotted lines and fold in the middle.

Antithrombin (ATryn) is a ________ type of protein.

Answer: recombinant

Thawed, pooled, milk is diluted with EDTA buffer,

and clarified by_________

Answer:

Tangential Flow Filtration

Which types of particles are removed from the milk

by TFF? Answer: Colloidal

Which type of column filtration is used in the upstream process of

ATryn?

Answer: Heparin Affinity

_____ chromatography is the ultimate goal of

purification - to recognize only the protein of interest.

Answer: Affinity

Hydrophobic means that the medium _______ water

Answer: Does not like / dislike

_________ separates by size.

Answer: Filtration

One process involved in Upstream processing is

cell manipulation by_______

Answer: recombinant DNA technology

The size of a macromolecule can be

estimated by calculating the ________ radius.

Answer: Stokes-Einstein

Mention one type of mass transfer.

Answer: Diffusive (molecular) / Convective

A filter retains _____ and allows passage of ______

Answer: retentate, filtrate or permeate

Membranes can be manufactured from either

______ or ______ materials.

Answer: organic, inorganic

Precipitation based Bioseparation is the _____

of a specific dissolved component of complex mixtures to an insoluble

form.

Answer: selective conversion

Precipitation can be dependent upon the

______ or _____ of the solution.

Answer: temperature, pH

The most common precipitation method is the ____for purifying plasma

proteins.

Answer: Cohn fractionation

Crystallization is a ______type of precipitation.

Answer: special

______ salts are used in DNA and RNA purification

since they precipitate proteins but leave nucleic acid molecules unaffected.

Answer: Chaotropic

Mention one type of cell that is disrupted by

bioprocessing.

Answer: Gram positive bacterial / Gram negative bacterial / Yeast / Mold / Cultured mammalian / cultured plant / Ground

tissue

Mention one category for cell disruption methods.

Answer: Physical / Chemical

Nucleic acids such as DNA and RNA are ________

molecules. Answer: linear

White Section – Mystery questions:

Cut along the dotted lines and fold in the middle.

ATryn manufacture process can be categorized as __________

bioprocessing.

Answer: extractive

Bioprocessing is the _______ such as bio-

chemicals, pharmaceuticals, foods,

food additives, nutraceuticals, agrochemicals

Answer: manufacture of biological products

Mention one utilization of Bioseparations

Engineering principles for biological products

manufacturing.

Answer: Recovery, Isolation, Purification, Polishing

The first step in cell fractionation and protein

purification is called_______

Answer: cell lysis

____________detergent is preferred for bioprocessing

Answer: Nonionic / Non-ionic

Mention one type of transport phenomena

Answer: Heat transfer / Fluid flow / Mass transfer

Mention one of the biologically derived

products that can be separated by Bioseparation

techniques.

Answer: Solvents / Organic Acids / Vitamins / Amino

acids / Sugars / Carbohydrates / Lipids /

Nucleic acids / semi-purified proteins / purified proteins / cells / crude cellular extracts

/ Hydrolysates

Biological products are separated based on few

factors. Mention one.

Answer: Size / Density / Diffusivity / Shape / Polarity /

Solubility / Electrostatic Charge / Volatility

What is RIPP?

Answer: Recovery, Isolation, Purification, and Polishing, scheme commonly used in

Bioseparation.

Bioseparations in mainly based on __________ separation processes.

Answer: chemical

Topic Two – Learn about regulations on validation and documentation

Review FDA CDER/CBER Q9 Quality Risk Management guidance for industry on the world wide web. Students

present five minute power point presentations on assigned Q9 sections. (Number of days required to accomplish

this will vary dependent on class size and class period. We allot one day in this schedule assuming a class size of

ten or less for a 75 minute class period).

Review Pharmaceutical Inspection Co-operation Scheme recommendation on Quality system Requirements –

documentation, change control and records on the world wide web. Students to discuss in Blackboard discussion

board and respond to at least two of their classmates “What are the three most important points you learned in

reading this portion of PICScheme and why?”

Lecture on process validation.

Topic Three – Learn about process validation.

Lectures continue on process validation, including that of biotechnology processes.

Assignment to read article Flanigan, Tim & Mackey, Robert; Streamlining the Validation Process, Chemical

Engineering Progress, March 2007, 48-52.

Students to discuss in Blackboard discussion board and respond to at least two of their classmates “At what point

in the development of a new biotechnology product should validation be considered and why?”

Quiz on biotechnology process validation.

Topic Four – Learn about documentation methods for process validation

Review Process Validation procedure VAL -106 template provided by Jesse Gillikin, President and CEO of

cGMP Validation. (contact Stephanie Sullivan, East Carolina University at [email protected] for template).

Topic Five – Learn about use of statistics in process validation

Provide reading assignment on advanced statistical techniques for biotechnology. Students to submit outline and

description of techniques discussed in the article and their importance. Lee, Kwang-Min & Gilmore, David F.;

Statistical Experimental Design for Bioprocess Modeling and Optimization Analysis. Applied Biochemistry and

Biotechnology (2006) 135, p. 101-115.

Provide reading assignment on advanced statistical techniques for biotechnology. Students discuss article in

class.

Students to submit outline and description of techniques discussed in the article and their importance in MS Word

document. Wang, Xiangyang, Germansderfer, Abe, Harms, Jean; and Rathore, Anurag S. (Process Development

and Corporate Quality Engineering, Amgen Inc.) Using Statistical Analysis for Setting Process Validation

Acceptance Criteria for Biotech Products. Biotechnology Progress (2007) 23(1), p. 55-60. Students discuss

article in class.

Test your Mettle: You Lead Marketing Designers in the marketing department of a large biopharmaceutical

company. You have been asked to research, develop and design a poster about the production, quality and safety

of a bioproduct. This poster will be used to market a planned new product at health fairs around the country, and

thus should be something that Miss Wormwood would understand, but uses and defines terms from this course.

Your ability to teach/communicate to the poster reader in terms a lay person can understand will show your grasp

of the material. Some resources are included here for your information. You should use some of these resources,

but are not limited to using only these. You are highly encouraged to use any outside resources available to you

(other than other classmates). Just as in the preparation of a research paper, citing resources and providing a

bibliography on the poster is required with APA format. Please complete this assignment using MS Power Point

software. A poster template provided in Bb. Please include images and figures where appropriate (one good

source is http://images.google.com), including data that may be pertinent to show the product's safety and

efficacy.

Go Public: Develop a Process Validation Protocol for the BIOE 4010 Ethanol laboratory (for which you prepared

a laboratory procedure). Use the process validation procedure VAL -106 as your guide. You may use as

resources material provided for this module as well as additional library resources such as books or journal

articles (cite all references).

Below is the suggested time line for the Process Validation Legacy Cycle. After using it as an overview to plan out

lessons, you can also make a copy to mark up and use as a checklist to keep track of what things your class has completed.

This can be especially useful if you have multiple classes working through the challenge, as multiple classes are seldom at

the same place at the same time in a series of lesson.

page(s) DAY ONE

• Introduce the challenge.

• Have the students independently work in their journals to answer the Generate Ideas

questions. If possible, have journal responses submitted electronically so that all

entries can easily be pulled into one document.

• As a class, review all journal entries.

• On the board, record the needed knowledge areas that students identified. Also

record any specific ideas that were generated.

• Read multiple perspective provided as a class.

• Assignment to read Review Scientific American & Trends in Biotechnology articles

on recombinant proteins.

DAY TWO • Discuss main points of recombinant protein articles

• Recombinant therapeutic protein process game

• Assignment to read FDA CDER/CBER Q9 Quality Risk Management guidance for

industry and develop power point presentations on assigned section.

DAY THREE

• Students present five minute power point presentations on assigned Q9 sections.

(Number of days required to accomplish this will vary dependent on class size. We

allot one day in this schedule assuming a class size of ten or less)

• Assignment to read Pharmaceutical Inspection Co-operation Scheme

recommendation on Quality system Requirements – documentation, change control

and records. Students to discuss in Blackboard discussion board and respond to at

least two of their classmates “What are the three most important points you learned

in reading this portion of PICScheme and why?”

DAY FOUR

• Lecture on process validation.

History of validation

Process validation defined;

Critical Process Parameters and Critical Quality Attributes

• Introduce “test your mettle” poster assignment. Provide the requirements of and

guidelines for the poster. Assignment to be accomplished by teams of 2-3 students.

DAY FIVE

• Lecture on process validation.

Validation of solid dosage forms – processes and issues

• Assignment to read article Flanigan, Tim & Mackey, Robert; Streamlining the

Validation Process, Chemical Engineering Progress, March 2007, 48-52. Students

to discuss in Blackboard discussion board and respond to at least two of their

classmates “At what point in the development of a new biotechnology product

should validation be considered and why?”

DAY SIX

• Lecture on process validation continued

Validation of biotechnology processes – processes and issues

DAY SEVEN

• Quiz on biotechnology process validation.

• Introduce “go public” assignment, providing ethanol production process lab manual

(or if Module 4 is used, students are to utilize what they developed for the “go

public” lab manual assignment). Review Process Validation procedure VAL -106

template provided by Jesse Gillikin, President and CEO of cGMP Validation.

DAY EIGHT

• Protein product health fair expo. Students present and review posters (10 minute

presentations). Class votes on the product they would most likely want to use based

on the poster and presentation.

• Provide reading assignment on advanced statistical techniques for biotechnology.

Students to submit outline and description of techniques discussed in the article and

their importance in MS Word document. Lee, Kwang-Min & Gilmore, David F.;

Statistical Experimental Design for Bioprocess Modeling and Optimization

Analysis. Applied Biochemistry and Biotechnology (2006) 135, p. 101-115.

DAY NINE

• Lecture on Statistical Methods for Uniformity & Dissolution Testing

• Discuss Lee et al. reading assignment.

• Provide reading assignment on advanced statistical techniques for biotechnology.

Students to submit outline and description of techniques discussed in the article and

their importance in MS Word document. Wang, Xiangyang, Germansderfer, Abe,

Harms, Jean; and Rathore, Anurag S. (Process Development and Corporate Quality

Engineering, Amgen Inc.) Using Statistical Analysis for Setting Process Validation

Acceptance Criteria for Biotech Products. Biotechnology Progress (2007) 23(1), p.

55-60.

DAY TEN

• Lecture on Statistical Methods for Uniformity & Dissolution Testing

Example using solid dosage form manufacturing.

• Discuss Wang et al. reading assignment

• Submit “go public”