Chemistry, Manufacturing and Controls of NDA's

The other day, my wife asked me a what if question. She ask that if I have a chance and be granted a wish, would I be willing to take back my job as a Chemistry Team Leader for the Food and Drug Administration since my mind is still sharp. Without hesitation I said no and explained to her about the two facets of my responsibilities as a first line supervisor in charge of the Chemistry, Manufacturing and Control requirements for a New Drug Application (NDA) in the Division of Anti-Infective Drug Products.

The first facet is my interaction with Chemists and Reviewers under my supervision and from other Divisions. I will have no problem handling that today. The second facet is my interaction with the representatives of the Pharmaceutical companies that FDA regulates. This facet requires up to date knowledge of laws, regulations and Guidances. Today, I feel I will not be as sharp and well-prepared to this part of my responsibilities if I am still a Chemistry Team Leader for FDA. There are 43 CMC Guidances that a team leader should know by heart and mind. At this stage of my life, I believe I will not be able to handle the pressure and responsibilities on this facet of a team leader job.

In my previous posting, I discuss a general overview of new drug development(NDA) and FDA's role in the process. In this article I am focusing on the Chemistry portion of a new drug application which was my expertise when I was still working for FDA from September,1990 up to October,2002. I am listing below a table of all CMC Guidances both in draft and final form. As a former Chemistry team leader in the Division of Anti-Infectives Drug Products in the Center of New Drugs Chemistry, I have some input on the contents of a few of these guidances. These 43 guidances are available in the Internet for everyone.

Below is a table of Chemistry, Manufacturing and Controls (CMC) Guidances showing,
category, title status( draft or final) and date.

1. Chemistry, Manufacturing, and Controls (CMC) Analytical Procedures and Methods Validation (PDF - 91KB)1 Draft Guidance 08/30/00

2. Chemistry, Manufacturing, and Controls (CMC) Assay Development for Immunogenicity Testing of Therapeutic Proteins (PDF - 161KB)2 Draft Guidance 12/04/09

3. Chemistry, Manufacturing, and Controls (CMC) Botanical Drug Products (PDF - 437KB)3 Final Guidance 06/01/04

4. Chemistry, Manufacturing, and Controls (CMC) Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (PDF - 33KB)4 Final Guidance 07/01/97

5. Chemistry, Manufacturing, and Controls (CMC) Changes to an Approved NDA or ANDA (PDF - 108KB)5 Final Guidance 04/01/04

6. Chemistry, Manufacturing, and Controls (CMC) Changes to an Approved NDA or ANDA: Questions and Answers (PDF - 35KB)6 Final Guidance 01/01/01

7. Chemistry, Manufacturing, and Controls (CMC) Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for Compendial Changes (PDF - 18KB)7 Final Guidance 11/19/04

8. Chemistry, Manufacturing, and Controls (CMC) CMC Postapproval Manufacturing Changes Reportable in Annual Reports (PDF - 78KB)8 Draft Guidance 06/24/10

9. Chemistry, Manufacturing, and Controls (CMC) Comparability Protocols -- Chemistry, Manufacturing, and Controls Information (PDF - 240KB)9 Draft Guidance 02/25/03

10. Chemistry, Manufacturing, and Controls (CMC) Container Closure Systems for Packaging Human Drugs and Biologics (PDF - 164KB)10 Final Guidance 05/01/99

11.Chemistry, Manufacturing, and Controls (CMC) Container Closure Systems for
Packaging Human Drugs and Biologics -- Questions and Answers (PDF - 15KB)11 Final Guidance 05/01/02

12. Chemistry, Manufacturing, and Controls (CMC) Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products12 Final Guidance 04/01/96

13, Chemistry, Manufacturing, and Controls (CMC) Development of New Stereoisomeric Drugs13 Final Guidance 05/01/92

14. Chemistry, Manufacturing and Controls (CMC) Drug Master Files (DMFs)14 Additional Information regarding DMF's

15. Chemistry, Manufacturing, and Controls (CMC) Drug Master Files for Bulk Antibiotic Drug Substances (PDF - 23KB)15 Final Guidance 11/01/99

16. Chemistry, Manufacturing, and Controls (CMC) Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals (PDF - 88KB) Draft Guidance 09/11/02

17. Chemistry, Manufacturing, and Controls (CMC) Environmental Assessment of Human Drug and Biologics Applications (PDF - 188KB)17 Final Guidance 07/01/98

18. Chemistry, Manufacturing, and Controls (CMC) Format and Content for the CMC Section of an Annual Report (PDF - 29KB)18 Final Guidance 09/01/94

19. Chemistry, Manufacturing, and Controls (CMC) Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting (PDF - 79KB)19 Draft Guidance 07/14/09

20. Chemistry, Manufacturing, and Controls (CMC) INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information (PDF - 193KB)20 Final Guidance 05/20/03

21. Chemistry, Manufacturing, and Controls (CMC) IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and Controls Information (PDF - 30KB)21 Final Guidance 05/01/01

22. Guidance for Industry: Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations (PDF - 26KB)22

23. Chemistry, Manufacturing, and Controls (CMC) Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation (PDF - 45KB)23 Draft Guidance 08/21/02

24. Chemistry, Manufacturing, and Controls (CMC) Monoclonal Antibodies Used as Reagents in Drug Manufacturing (PDF - 29KB)24 Final Guidance 03/01/01

25. Chemistry, Manufacturing, and Controls (CMC) Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products (PDF - 361KB)25 Draft Guidance 11/19/98

26. Chemistry, Manufacturing, and Controls (CMC) Nasal Spray and Inhalation Solution, Suspension, and Drug Products (PDF - 116KB)26 Final Guidance 07/01/02

27. Chemistry, Manufacturing, and Controls (CMC) NDAs: Impurities in Drug Substances (PDF - 11KB)27 Final Guidance 02/01/00

28. Chemistry, Manufacturing, and Controls (CMC) Orally Disintegrating Tablets (PDF - 52KB)28 Final Guidance 12/17/08

29. Chemistry, Manufacturing, and Controls (CMC) PAC-ATLS: Postapproval Changes - Analytical Testing Laboratory Sites (PDF - 76KB)29 Final Guidance 04/28/98

30. Chemistry, Manufacturing, and Controls (CMC) Residual Drug in Transdermal and Related Drug Delivery Systems (PDF - 44KB)30 Draft Guidance 08/02/10

31. Chemistry, Manufacturing, and Controls (CMC) Residual Solvents in Drug Products Marketed in the United States (PDF - 52KB)31 Final Guidance 11/24/09

32. Chemistry, Manufacturing, and Controls (CMC) Reviewer Guidance, Validation of Chromatographic Methods (PDF - 703KB)32 Final Guidance 11/01/94

33. Chemistry, Manufacturing, and Controls (CMC) Size of Beads in Drug Products Labeled for Sprinkle (PDF - 43KB)33 Draft Guidance 01/18/11

34. Chemistry, Manufacturing, and Controls (CMC) Submitting Documentation for the Manufacturing of and Controls for Drug Products (PDF - 1048KB)34 Final Guidance 02/01/87

35. Chemistry, Manufacturing, and Controls (CMC) Guidelines for Submitting Samples and Analytical Data for Methods Validation Final Guidance 02/01/87

36. Chemistry, Manufacturing, and Controls (CMC) Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (PDF - 94KB)36 Final Guidance 02/01/87

37. Chemistry, Manufacturing, and Controls (CMC) SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (PDF - 60KB)37 Final Guidance 11/01/95

38. Chemistry, Manufacturing, and Controls (CMC) SUPAC-IR Questions and Answers about SUPAC-IR Guidance38 Final Guidance 02/18/97

39. Chemistry, Manufacturing, and Controls (CMC) SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms Manufacturing Equipment Addendum (PDF - 117KB)39 Final Guidance 01/01/99

40. Chemistry, Manufacturing, and Controls (CMC) SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (PDF - 215KB)40 Final Guidance 10/06/97

41. Chemistry, Manufacturing, and Controls (CMC) SUPAC-SS: Nonsterile Semisolid Dosage Forms Manufacturing Equipment Addendum (PDF - 61KB)41 Draft Guidance 12/01/98

42. Chemistry, Manufacturing, and Controls (CMC) SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (PDF - 118KB)42 Final Guidance 05/01/97

43. Guidance for Industry - The Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use The Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use 09/01/97

Note: As a Chemistry Team Leader, you need to be familiar with contents of these 43 Guidances, so when representatives from the Pharmaceutical firms ask you a question, you should be able to refer them to the guidance. If you can answer their question
without referring to the guidance, the firm's representative look at you with high regard and respect. It is therefore imperative that you know most of the important requirements for an New Drug application (NDA) submission as well as the post NDA requirements in the manufacture, chemistry and controls of an Investigational New Drug (IND) or NDA. A Guidance is not a Federal Regulation/Law. The 21CFR (Code of Federal Regulation), gives FDA mandate to enforce drug and food laws in US.

Source: www.fda.gov

A Simple Crab Quiche Recipe

Due to the abundance and reasonably price( only $3.99/lb) fresh Dungeness Crabs this week here in Northern California, I was able to experiment preparing several dishes using crab meat. I have prepared crab omelet, corn and crab soup and crab cakes. Today I am experimenting on preparing my first crab quiche recipe. The following is the simplest I found in the Web.

1/2 cup mayonnaise

2 tablespoons all-purpose flour

2 eggs, beaten

1/2 cup milk

1 cup crab meat

1 cup diced Swiss cheese

1/2 cup chopped green onions

1 (9 inch) unbaked pie crust


Preheat oven to 350 degrees F (175 degrees C). In a medium bowl, beat together eggs, mayonnaise, flour, and milk until thoroughly blended. Stir in crab, cheese, and onion. Spread into pie shell. Bake for 40 to 45 minutes, or until a knife inserted in the center comes out clean. Enjoy and Bon Apetit!

Reference: allrecipes.com

My Favorite Crab Cake Recipe

I was searching for the simplest crab cake recipe in the Web with a lot of crab meat and less additives. I found this classic Maryland crab recipe by Susie Middleton published at Fine Cooking Magazine. The only additive is the breadcrumbs. With the abundance of Dungeness Crab this week here in Northern California, I was able to purchase 4 whole 1.5-pounder Dungeness Crabs from Food Max at only $3.99/lb the other day. I believe this will be the cheapest price the crab market will allow based on historical data of the crab season here in California.

This was my first time to prepare crab cakes, but the recipe looks very simple. The hardest part was cleaning the crab. It took me about an hour to harvest about one pound of meat from the two whole crabs bodies and claws. My neck started to strain from the concentration of extracting the meat from the crab shells and claws. If you are lazy, and have no time or patience to extract the meat from the whole crab, you can purchase fresh and pasteurized meat. The disadvantages are that you will miss the butter or fat of the crab and you will pay much higher for your meat. For example a 4 oz of lump meat cost about $21.99 in Safeway.

After tasting the recipe below, I will prepare it again perhaps next year Dungeness Crab season. If the price of Dungeness Crab is still $3.99/lb next week, I plan on cooking another crab omelet, a crab quiche, a crab garden salad Louie and may be another crab cake dish again. Bon Apetit!

1 lb. crabmeat, fresh or pasteurized ( Dungeness, Maryland or Philippines)
1 large egg
1/4 cup mayonnaise
1-1/2 tsp. Dijon mustard
1-1/2 tsp. Old Bay seasoning
1 tsp. fresh lemon juice
1/2 tsp. Worcestershire sauce Kosher salt
1-1/4 cups fresh breadcrumbs (from soft white sandwich bread)
1 Tbs. chopped fresh flat-leaf parsley
2 Tbs. unsalted butter
1 Tbs. olive oil
Lemon wedges for serving

Drain the crabmeat, if necessary, and pick through it for shells. Put the crab in a medium mixing bowl and set aside.

In a small bowl, whisk the egg, mayonnaise, mustard, Old Bay seasoning, lemon juice, Worcestershire sauce, and 1/4 tsp. salt. Scrape the mixture over the crab and mix gently until well combined. Gently break up the lumps with your fingers but do not overmix.

Sprinkle the breadcrumbs and the parsley over the mixture, and mix them in thoroughly but gently; try not to turn the mixture into a mash—it should still be somewhat loose. Cover with plastic wrap and refrigerate for 1 to 3 hours.

Shape the crab mixture into 8 cakes about 1 inch thick. In a 12-inch nonstick skillet, heat the butter with the olive oil over medium heat. When the butter is frothy, add the cakes to the pan (8 should fit comfortably). Cook until dark golden brown on the underside, about 4 minutes. Flip the cakes, reduce the heat to medium low, and continue cooking until the other side is well browned, 4 to 5 minutes. Serve with lemon wedges on the side for squeezing over the cakes.

Reference: www.finecooking.com/classicmarylandcrabcake/Photo by Scott Philip

Another Scam Letter Capitalizing on the Popularity of FaceBook

I received the following in my eMail today. It is very convincing, but originating from West Africa smells of rotten fish, although the origin of the letter is supposed to be in Menlo Park. The street address of #1 Hacker Way sounds very appropriate.

FACEBOOK INTERNATIONAL LOTTERY AWARD 2013
The Online FaceBook Consumer's Promotions 2013.
Facebook Corporate Office Headquarters HQ
#1 Hacker Way, Menlo Park,
California 94025 USA
Official Website: www.facebook.com

Dear Sir/Madam,

Congratulations We Are Happy To Inform You That Your Email Address
Have Won $500,000.00 (Five Hundred Thousand Dollars) From FaceBook
International Christmas Lottery Award 2013.

This Lottery is sponsored and promoted by the FaceBook International
Lottery Award U.S.A as the part of COMMUNICATION around the World and
to promote the use of INTERNET in the world, no tickets were sold but
all E-mail addresses were assigned to different ticket numbers for
representation and privacy. Your E-mail Access Code: 101 to avoid
Scam/Fraud lottery going on internet.

(WINNING NOTIFICATION NUMBERS)
TICKET NUMBER: 00545 188 564756
WINNING NUMBER: FB/575061725
PRIZE NUMBER: 7780129/N
SERIAL NUMBER: 5368/02

FILL YOUR PERSONAL INFORMATION AND SUMMIT TO YOUR REGIONAL CLAIMS
AGENT IN WEST AFRICA NIGERIA (REV. JOHN TIMOTHY) FOR MORE DETAILS AND
DIRECTIVES FOR CLAIMS.

1.Full Name:
2.Full Address:
3.Marital Status:
4.Occupation:
5.Age:
6.Sex:
7.Nationality:
8.Amount Won:
9.Mobile Phone Number:
10.Your lucky email address:
"""""""""""""""""""""""""""""""""""""""""""""
Rev. John Timothy
Email: rev.johntimothy2013@live.com
Phone Number: +234-80323-06470
"""""""""""""""""""""""""""""""""""""""""""""
NOTE: Keep your winning private from public to avoid double claim and
unwarranted taking of advantage because it will lead to
disqualifications.

Yours in service,
Prof. Wilcox Bruce
Award Co-ordinator
FaceBook International Lottery Board USA.

Bird Watching in My Backyard in Marinduque

December 1, is the official first day of bird watching in the beautiful Island of Marinduque-Our Second Home!
The Cuckoo Bird in my backyard, Chateau Du Mer, Boac, Marinduque, Philippines

Marinduque Island, Philippines is a tourist destination for Bird watchers all over the world. In my backyard at Chateau Du Mer, you can watch several species of wild birds that reside in the gardens and flowering trees in my back yard orchard. Besides bird watching, one can enjoy beach walking and snorkeling at the resort as well as caving, biking and touring the butterfly farms nearby.
Yellow Breasted Bird
What is this Bird's Name?
For the last four months this year and last year while we were in Marinduque, Macrine and I had been enjoying watching the beautiful wild birds that resides in the gardens and fruit trees of Chateau Du Mer. I do not know most of the bird names except for one, they called "the cuckoo", because of the sounds the bird makes. This bird had a long tail, blackish-brown almost look like a small parrot and very elusive. It flies from the tamarind tree in our back porch to the huge palm tree by the side of the house. It hides in the thick foliage of the trees, so unless you look closer, you may not be able to see this beautiful wild bird. Another bird is multicolored and almost look like the California blue Jay but with a yellow breast but blue throat. It is smaller than the cuckoo, but this one would stay on our clotheslines for minutes and you can enjoyed watching its beautiful plumage for a long while. Besides the above two birds, there several varieties of birds, butterflies, and bees that also reside in the gardens and fruit trees of Chateau Du Mer.

Just recently, I found out that there are bird sanctuaries in Marinduque. The bird wildlife adventure organization of the world listed the following birds that can be watched in the six towns of the province as follows:

Amethyst Brown-dove, Blackish Cuckoo-shrike, White-browed Shama, Mangrove Blue Flycatcher, Purple-throated Sunbird, Mountain White-eye Zosterops, Philippine Duck, Philippine Cockatoo and Green Racquet-tail.

Other activities recommended by the group besides Bird Watching are, Caving, Trekking and Camping. The seashores near Chateau Du Mer is excellent for bathing and snorkeling as well as jogging or just beach walking/combing. Chateau Du Mer Beach Resort and Conference Center is located in Western Marinduque, 8 KM from downtown Boac- the capital town of Marinduque.

Marinduque Wildlife Sanctuary regions are located on the western side of Gasan, northeast side of Sta. Cruz, southern side of Buenavista, northwest side of Boac and at the eastern side of Torrijos.

The best time of the year for bird watching is from December 1 to May 30. For details, visit www.world-wildlife-adventures.com. As Marinduquenos, we should do our best to help in the conservation of these wild birds. They are our national treasures.