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Getting to know 21 cfr 210 and 211 by micah thomas with speaker notes update 2021
- 1. GETTING TO KNOW 21 CFR 210/211 current Good Manufacturing Practice (cGMP) Presented by Micah Thomas 1
- 2. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. GMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 2
- 3. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. GMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 3
- 4. www.usp.org ■ Nonprofit Organization ■ Sets standards for identity, strength, quality and purity of medicines, food ingredients, and dietary supplements ■ USP’s drug standards are enforceable in the United States by the Food and Drug Administration 4
- 6. United States Pharmacopeia – National Formulary (USP-NF) ■ Combination of two compendia, the United States Pharmacopeia (USP) and the National Formulary (NF) ■ Contents: – USP : Monographs for drug substances, dosage forms and compounded preparations – NF : Monographs for excipients – General Chapters: Tests and Procedures – General Notices: Definitions 6
- 7. 7 Example of USP-NF Monograph ■ Contents: • Name of (Drug Substance or Excipient) • Definition • Specifications • Packaging & storage • Labeling requirements
- 8. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. GMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 8
- 9. Pure Food and Drug Act (1906) ■ First of a series of consumer protection laws enacted by Congress and signed into law by President Theodore Roosevelt ■ Its main purpose was to ban foreign and interstate traffic of adulterated or mislabeled food and drug products. ■ In principal the law was a “truth in labeling” law. It required that active ingredients be placed on the label. ■ It also required that drugs could not fall below the purity levels established by the USP-NF. 9 Also know as the “Wiley Act” Harvey Washington Wiley, M.D.
- 10. 10 FDA History - Photo Album
- 11. 11 FDA History - Photo Album
- 12. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. GMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 12
- 13. Food & Drug Administration www.fda.gov ■ 1848 - Patent Office ■ 1862 - U.S. Department of Agriculture – Division of Chemistry (later Bureau of Chemistry) ■ 1927 - Food, Drug and Insecticide Organization was created to reorganize the regulatory powers of the Bureau of Chemistry ■ 1930 – Food and Drug Administration 13
- 14. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. GMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 14
- 16. Federal Food, Drug and Cosmetics Act (1938) ■ Required companies to perform animal safety testing on proposed drugs and submit data to the FDA. ■ Replaced the earlier Pure Food and Drug Act of 1906. ■ The FDC Act has 10 chapters – I. Short Title – II. Definitions – III. Prohibited Acts and Penalties – IV. Food – V. Drugs and Devices – VI. Cosmetics – VII. General Authority – VIII. Imports and Exports – IX. Tobacco Products – X. Miscellaneous 16 Franklin D. Roosevelt signing the 1938 Food, Drug and Cosmetics Act
- 17. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. cGMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 17
- 18. First U.S. GMP regulations established (1963) 18
- 19. 19 CFR : Code of Federal Regulations TITLE 21 : Food and Drugs CHAPTER 1: Food and Drug Administration Department of Health and Human Services SUB-CHAPTER C: Drugs: General PART 210: Current Good Manufacturing Practices In Manufacturing, Processing, Packaging, or Holding of Drugs; General PART 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
- 20. 20 www.fda.gov
- 21. 21
- 22. 22
- 23. 23
- 24. 24
- 25. Part 210 current Good Manufacturing Practice in Manufacturing, Processing, Packaging, or Holding of Drugs; General § 210.1 – Status of current good manufacturing practice regulations. § 210.2 – Applicability of current good manufacturing practice regulations. § 210.3 – Definitions. 25
- 26. 210.3 Definitions (b)(2) Batch (3) Component (4) Drug product (5) Fiber (6) Non-fiber releasing filter (7) Active ingredient (8) Inactive ingredient (9) In-process material (10) Lot (11) Lot number (12) Manufacture, processing, packaging or holding of a drug product (15) Quality control unit (16) Strength (17) Theoretical yield (18) Actual yield (19) Percentage of theoretical yield (20) Acceptance criteria (21) Representative sample (22) Gang-printed labeling 26
- 27. Part 211 current Good Manufacturing Practice for Finished Pharmaceuticals 27 G – Packaging and Labeling Control H – Holding and Distribution I – Laboratory Controls J – Records and Reports K – Returned and Salvaged Drug Product Subpart A – General Provisions B – Organization and Personnel C – Building and Facilities D – Equipment E – Control of Components and Drug Product Containers and Closures F – Production and Process Controls
- 28. Subpart A– General Provisions § 211.1 - Scope. (a) The regulations in this part contain the minimum current good manufacturing practices for preparation of drug products (excluding positron emission tomography drugs) for administration to humans and animals. § 211.3 - Definitions. The definitions set forth in 210.3 of this chapter apply to this part. 28
- 29. Subpart B – Organization and Personnel § 211.22 - Responsibilities of quality control unit. § 211.25 - Personnel qualifications. § 211.28 - Personnel responsibilities. § 211.34 - Consultants. 29
- 30. Subpart C – Buildings and Facilities § 211.42 - Design and construction features. § 211.44 - Lighting. § 211.46 - Ventilation, air filtration, air heating and cooling. § 211.48 - Plumbing. § 211.50 - Sewage and refuse. § 211.52 - Washing and toilet facilities. § 211.56 - Sanitation. § 211.58 - Maintenance. 30
- 31. Subpart D - Equipment § 211.63 - Equipment design, size, and location. § 211.65 - Equipment construction. § 211.67 - Equipment cleaning and maintenance. § 211.68 - Automatic, mechanical, and electronic equipment. § 211.72 - Filters. 31
- 32. Subpart E – Control of Components and Drug Product Containers and Closures § 211.80 - General requirements. § 211.82 - Receipt and storage of untested components, drug product containers, and closures. § 211.84 - Testing and approval or rejection of components, drug product containers, and closures. § 211.86 - Use of approved components, drug product containers, and closures. § 211.87 - Retesting of approved components, drug product containers, and closures. § 211.89 - Rejected components, drug product containers, and closures. § 211.94 - Drug product containers and closures. 32
- 33. Subpart F – Production and Process Controls § 211.100 - Written procedures; deviations. § 211.101 - Charge-in of components. § 211.103 - Calculation of yield. § 211.105 - Equipment identification. § 211.110 - Sampling and testing of in-process materials and drug products. § 211.111 - Time limitations on production. § 211.113 - Control of microbiological contamination. § 211.115 - Reprocessing. 33
- 34. Subpart G – Packaging and Labeling Control § 211.122 - Materials examination and usage criteria. § 211.125 - Labeling issuance. § 211.130 - Packaging and labeling operations. § 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. § 211.134 - Drug product inspection. § 211.137 - Expiration dating. 34
- 35. Subpart H – Holding and Distribution § 211.142 - Warehousing procedures. § 211.150 - Distribution procedures. 35
- 36. Subpart I – Laboratory Controls § 211.160 - General requirements. § 211.165 - Testing and release for distribution. § 211.166 - Stability testing. § 211.167 - Special testing requirements. § 211.170 - Reserve samples. § 211.173 - Laboratory animals. § 211.176 - Penicillin contamination. 36
- 37. Subpart J – Records and Reports § 211.180 - General requirements. § 211.182 - Equipment cleaning and use log. § 211.184 - Component, drug product container, closure, and labeling records. § 211.186 - Master production and control records. § 211.188 - Batch production and control records. § 211.192 - Production record review. § 211.194 - Laboratory records. § 211.196 - Distribution records. § 211.198 - Complaint files. 37
- 38. Subpart K – Returned and Salvaged Drug Products § 211.204 - Returned drug products. § 211.208 - Drug product salvaging. 38
- 39. 39
- 40. 40
- 41. United States Pharmacopeial Convention 1820 Pure Food & Drugs Act 1906 Food & Drug Administration (FDA) 1930 U.S. GMP 1963 International Council for Harmonization (ICH) 1990 Federal Food, Drug & Cosmetic Act 1938 TIME LINE 41
- 42. International Council for Harmonization (ICH) www.ich.org ■ There was a recognized need for harmonization with rapid increase of laws, regulations and guidelines during the 1960-1970s. Initiated by the European Community (EC), now European Union (EU), in the 1980s. Bilateral discussions began between the EC, U.S. and Japan. ■ Established in 1990 the Steering Committee of ICH decided the topics for harmonization would include Safety, Quality, and Efficacy. These topics are the basis for approving and authorizing new medicinal products. 42
- 43. 43
- 44. 44
- 45. Tips ■ Pharmaceutical regulations and guidance documents are a collaborative effort in today’s global industry. ■ Part 210 and 211 describes the ‘WHAT’ you must do for regulatory compliance. ■ In order to find the ‘HOW’ to be compliant, look for industry guidance documents and information provided by the FDA and other organizations that are recognized by the FDA. ■ www.usp.org ■ www.fda.gov ■ www.ich.org ■ www.ispe.org Techniques 45
Editor's Notes
- I am going to cover some of the basics of the ‘WHAT’ and the ‘HOW’ of 21 CFR Part 210 and 211. You will often hear that current Good Manufacturing Practices cover the ‘WHAT’ you must do to be compliant but not the ‘HOW’ you are expected to achieve that compliance. And this is where some of the difficulty in understanding the expectations lie. Today, I will provide you some information on where to find both the ‘WHAT’ and the ‘HOW’. *next slide*
- In order to understand these regulations, it is important to understand the history of how we got to where we are today. I don’t want to spend a lot of our time providing a history lesson, nevertheless, some history is important to understanding the expectations the FDA has for compliance with cGMPs. *next slide*
- Let’s begin in 1820 with the United States Phamacopeial Convention *next slide*
- The United States Pharmacopeial Convention is a non-profit organization that was established around 1820. They set standards for identity, strength, quality and purity of medicines. Why are they relevant to this presentation today? Because the standards they set are enforceable by the FDA. They play an important role in the development, manufacturing, and testing of pharmaceuticals. This is where you can find some of the ‘HOW’ to achieve compliance. I’ve provided a link here to their web page. If you were to follow that link … *next slide*
- This is what you would see at their home page. There is a wealth of information provided here and I would encourage you to further explore their website on your own *click* but for now, I would like to focus on the selection highlighted in menu bar, under ‘Products & Services’, at the top of the page. The USP-NF *next slide*
- The USP-NF stands for the Unites States Pharmacopeia – National Formulary As I mentioned earlier, the FDA enforces the standards contained within this compendia – it is directly applicable to cGMPs with regards to manufacturing, testing and holding of drug products. It is a combination of two compendia, The 1st part - the USP, which contains monographs for drugs substances And the 2nd part - the NF, which contains monographs for excipients You might ask at this point what is a ‘drug substance’? It is often referred to as an Active Ingredient or Active Pharmaceutical Ingredient or simply (API), it is the ingredient in a Drug Product that is biologically active, it provides treatment for an indicated disease or condition. And you might also ask what is an ‘Excipient’? An excipient is an inactive ingredient that is combined with an API to form a Drug Product. Excipients can provide a number of different functions for the dosage form. The USP-NF also contains the General Chapters, which cover tests and procedures referenced in the monographs. It is important to note that the General Chapters section also contains other important information, like requirements for storage and distribution of drug products. And lastly General Notices, which contain definitions for terms used in the monographs. What is a ‘monograph’? *next slide*
- Here I have provided an example on the right, from the USP website. I realize you probably can’t see the details but - The monographs contain the Name and Definition of the drug substance or excipient, the Specification, which in this case means the required tests and acceptance criteria; and packaging, storage and labeling requirements. The expectation of the FDA, is that at a minimum you meet these standards. *next slide*
- Lets move on to 1906 and the Pure Food and Drug Act *next slide*
- This Act came into existence in 1906 after two decades of resistance by congress to federal regulation of food and drugs. It became a reality only after pressure from women’s groups of the time, journalists accounts of unsanitary food conditions, medicinal fraud, and a man named Harvey Wiley. Wiley was the Chief Chemist of the Bureau of Chemistry at the time and orchestrated the political support for passage of the Act. For this reason the Act is also known as the “Wiley Act”. The main purpose of the Act was to ban traffic of adulterated products. (You will run into the term ‘adulterated’ frequently when dealing with drug regulations. It has nothing to do with the 10 Commandments – In short – adulterated means “containing any substance which may render a product injurious to health”.) The Act required that active ingredients be placed on the label. And it is here, that we see the requirement, that purity levels can not fall below levels listed in the USP-NF. *next slide*
- On the next couple of slides, I have provided some examples of historical advertisements. I did this for a couple of reasons, 1- I find them rather amusing but 2- more importantly, to emphasize why regulations are necessary in our industry. In these cases, there may have not been an issue with the safety but the claims that were being made about the products may have have raised concerns. *click* In the first example for Vitamin donuts – they claim the donuts provide Pep and Vigor. *click* No-To-Bac - Kills the tobacco habit, sold and guaranteed by all druggists. *click* And one of my favorites Pratts Healing Ointment for Man and Beast- Cures harness and saddle galls, open wounds, cuts, sores, scratches, burns – every box guaranteed. *next slide*
- On this slide you will see two products, one for losing weight and another for gaining weight. *click* On this ad, how many people here can see what the “active ingredient” is for losing weight? Look toward the middle of the right side. (That’s right – sanitized tape worms). This is a real ad! *click* And if you want to gain some additional weight you could “Get fat on Loring’s Fat-Ten-U” If you find these ads amusing and/or informative, I’ve provided a link at the bottom of these pages to some additional historical photos the FDA has on Flickr. *next slide*
- Let’s move ahead to 1930. *next slide*
- This slide provides some history on how the FDA came into existence. *click* The origins of the FDA can be traced back to 1848 when Lewis Beck of the Patent Office began chemical analysis of agricultural products. *click* In 1862 the newly created USDA took over those responsibilities from the Patent Office. Within the USDA was the Division of Chemistry, later known as the Bureau of Chemistry, where testing was performed. As I mentioned earlier, Harvey Wiley became the Chief Chemist of the Bureau of Chemistry in 1882 and was largely responsible for the Pure Food and Drug Act of 1906. *click* In 1927 the Food, Drug and Insecticide Organization was created to reorganize the regulatory powers of the Bureau of Chemistry. *click* And in 1930 the name of the Food, Drug and Insecticide Organization was simply shortened to what we now know as the Food and Drug Administration, or the FDA. *next slide*
- One thing I would like to mention at this point is that most of these laws are reactionary. By that I mean that these Acts were put in place as a reaction to events of the time. For instance – *next slide*
- In September of 1937, the S.E. Massengill Company started marketing - Elixir sulfanilamide Harold Watkins, the chief chemist for the company, created this formulation using diethylene glycol as a solvent. Diethylene glycol is poisonous to humans. At the time animal testing was not required by law and there were no regulations requiring premarket safety testing of new drugs. By October 11th, 1937 the American Medical Association started receiving reports of fatalities and by the time the Elixir was identified as the cause and the product was pulled from the market over 100 people had died. The owner of the company, when pressed to admit responsibility was quoted as saying: “We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results.” Harold Watkins, the chemist, committed suicide while awaiting trial. The company paid a minimum fine under the 1906 Pure Food and Drug Act for labeling the formula as an elixir. At the time, it was prohibited to label something as an elixir if it did not contain alcohol. As a reaction to this and other tragedies of the time the Federal Food, Drug and Cosmetics Act was written into law. *next slide*
- It was this law that gave the FDA the authority to oversee the safety of food, drugs and cosmetics. It did this, in part, by requiring companies to perform premarket testing on new drugs and to submit the data to the FDA for review. *next slide*
- It wasn’t until 1963 that we saw the first Good Manufacturing Practice introduced. *next slide*
- Here we see many of the basic concepts that are part of our modern cGMPs today. Buildings, Equipment, Personnel, Components … and so on. *next slide*
- So what is the ‘Code of Federal Regulations’? The Code of Federal Regulations are the codification of Administrative Law – the CFR is legally binding. It is broken down into: *click* 50 subject matter titles. *click* Titles are broken down into chapters. Agencies are assigned to each of these chapters within the titles. *click* Chapters are broken down into sub-chapters, *click* And subchapters are broken down into Parts, sections and paragraphs. *next slide*
- I can not over emphasize the importance of the FDA’s website. There is so much information here that you can easily feel overwhelmed and lost. The search functions are not always intuitive but with a little practice you can narrow your results down to find the answers you want. I’m going to take you on a path to one of the search tools located within the FDA website. On this journey we will cross pages that contain other valuable information that will help you better understand and interpret these Administrative Laws within the CFR. Let’s begin the search for the ‘Code of Federal Regulations’. To begin your search, click on the ‘Menu’ tab at the upper right. Under ‘Topics’ you will see ‘Regulatory Information’, highlighted in red here, click here to continue. *next slide*
- Under the Regulatory Information page, you will see a link for ‘Rules & Regulations’ and a link for ‘Standards’, highlighted in red here. Our mission for now is to locate the CFR but I do want to point out that the ‘Standards’ link will bring you to yet another database search tool that is invaluable in understanding the ‘HOW’ to achieve compliance with the CFR. The ‘Standards’ link provides access to the Consensus Standards, which are recognized by the FDA. Some of this we will touch on further along in the presentation. For now, let’s move on to the ‘FDA Rules and Regulations’ page by clicking on that link. *click* *next slide*
- The FDA Rules and Regulations page provides some interesting links and information. It can be extremely helpful in interpreting the Administrative Laws by reading the ‘Notices and Comments Rulemaking’ materials. For now, lets continue to the CFR Databases, Under ‘CFR Resources’, you will find the links to the ‘21CFR Database on FDA.gov’, which is updated annually, as well as the ‘GPO Electronic Code of Federal Regulations (eCFR)’ highlighted in red here. I find that the search tool for the ’21 CFR Database on FDA.gov’ to be more useful, so let’s continue on that path by clicking on that link.
- Take a moment to review this page to better understand the search functions that will follow. 1. Search by Part and Section Number 2. Select a CFR Part Number 3. Full Text Search At the bottom of the page, you find a link ‘Search CFR 21 Database’, highlighted in red. Click here to continue to our destination.
- Here, under ‘Search Database’ *click* you can find all of the Parts of the CFR and *click* If you use the scroll bar under ‘Search Database’ you can access the details of each Part. Here I’ve highlighted Part 210 and 211. There are also helpful links on the right side of the page under ‘Other Databases’ *click* I want to call you attention to the ‘FDA Guidance Documents’ database, under ‘Other databases’ on the right. This link is also found on the FDA.gov home page, previously shown. *click* As I mentioned before, the CFR provides the ‘WHAT’ you need to do, and the FDA Guidance Documents are some of the ‘HOW’ you can meet those requirements. For now, let’s take a closer look at Part 210 and 211. *next slide*
- You will often find Part 210 and 211 lumped together but unfortunately not a lot of attention gets paid to Part 210. One thing you may notice about Part 210 is that the description is more encompassing than that of Part 211. The reason is that Part 210 is applicable not only to Part 211 but several other areas of the CFR as well. Here we see cGMPs as applicable to Manufacturing, Processing, Packaging, or Holding of Drugs. Part 211 is about cGMPs as they pertain to Finished Pharmaceuticals. It is important to note that cGMPs are applicable to other areas outside of Part 211’s Finished Pharmaceuticals. So, Part 210 - In general, the first two sections, 210.1 and 210.2, define the scope of cGMP regulations. It also has a section for Definitions (210.3), which provides 22 terms, most of which are applicable to Part 211. The Definitions section is particularly important, as these fundamental definitions will provide for better understanding of the regulations found in Part 211. *next slide*
- I am not going to provide you with these definitions here, this is something you will have to research on your own, but I have provided you with the terms that are applicable to Part 211. You will see some of these terms repeated throughout the Part 211 sections. Take a moment to look at some of these terms before we move on. *next slide*
- And now Part 211, I am not going to spend a lot of time going over the details of each of these subparts. We simply do not have the time today and with the time we do have I think it is more important to provide you with the information to know where to find these and the tools and information on ‘HOW’ to apply them. I will summarize and touch on some key points of the subparts. Part 211 has 11 subparts as seen here. It is very similar to the 1963 version we saw earlier. *next slide*
- Subpart A – General Provisions Scope - I think it is important to look at paragraph (a) of the first section of this subpart. The regulations in this part contain the minimum current good manufacturing practices for preparation of drug products for administration to humans and animals. (keep in mind, in this context the term ‘preparation’ is very broad) Definitions - The definitions section of this subpart simply refers to the previous definitions I just discussed in Part 210. *next slide*
- Subpart B – Organization and Personnel Responsibilities of quality control unit - The definition for ‘quality control unit’ is found in Part 210 and the responsibilities are listed here in this section. Personnel qualifications - The FDA has issued many findings for non-compliance to this section with regards to training and documentation of those activities. I would recommend being extra vigilant when it comes to maintaining your training systems. Many companies today rely on software such as ComplianceWire to support this requirement. Consultants - Keep in mind that qualification documentation is also required for Consultants that you may hire. *next slide*
- Subpart C – Buildings and Facilities Some key points regarding this subpart: Design and construction features - this section includes a requirement that there be separate or defined areas, or other control systems, for certain operations that are listed in this section, to prevent contamination or mix-ups. There are a lot of companies out there that do not provide adequate controls when it comes to this requirement. Sanitization - this section also contains requirements that are often not adequately maintained by companies. Not only is there a requirement for written procedures for cleaning the facilities but pest control is also a large part of this section. If you were to walk through a facility you should be able to see evidence of pest control, whether it be rodent traps, insect lights or barriers put in place to prevent access by pests. This is something that regulatory auditors look at closely and for good reason. *next slide*
- Subpart D - Equipment The equipment subpart has regulations that are specific to finished pharmaceuticals, as well as common regulations you will find in other industries. Equipment construction - requires that any surface of the equipment that comes into contact with components, in-process materials or drug products be non-reactive, non-additive or non-absorptive so as not to alter the safety, identity, strength, quality or purity of the drug product. Likewise, any substance used for operation of the equipment, such as lubricants or coolants must not come in contact with components, in-process materials or drug products so as to not alter the materials for the same reasons. Equipment cleaning and maintenance - as you might suspect, cleaning and maintenance of equipment used in the industry is not taken lightly. Regulatory auditors will thoroughly review the equipment and associated documentation required by this section. *next slide*
- Subpart E – Control of Components and Drug Product Containers and Closures Strict controls are required for components, drug product containers and closures. The definition for components is any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product. Drug product containers include bottles, vials, syringes, blister materials, any primary container that comes into contact with the drug product. And closures may include lidding material, caps, stoppers etc. *next slide*
- Subpart F – Production and Process Controls Written procedures and deviations - Of course, written procedures are big part of compliance in our industry and lack thereof is often cause for regulatory findings of non-compliance. For this reason the documentation management system, whether it be a hard copy or electronic system, is an essential quality system in our industry. Charge-in of components - this section assures that not less than 100% of the active ingredient is contained in a batch of drug product and that components are weighed, measured or subdivided as appropriate for the manufacture of the drug product. Calculation of yield - includes the calculation of actual yield and percent of theoretical yield (defined in Part 210). These calculations can be used as an indicator of a failure or problem in the manufacturing process and should be closely monitored. Equipment identification - not only requires that major equipment by identified as to its contents during manufacturing but also that the equipment have a unique identifier that is recorded in the batch records when used for manufacturing a drug product. This allows for traceability to the drug product in case a piece of equipment is later identified as non-compliant. Sampling and testing of in-process materials and drug products - this section assures batch uniformity and integrity of drug products. At a minimum, samples must be taken for – tablet or capsule weight variation; disintegration time; adequacy of mixing to assure uniformity and homogeneity; dissolution time and rate; clarity, completeness or pH of solutions; and bioburden testing. Time limitations on production - when appropriate, time limits for completion of each phase of production shall be established to assure quality of the drug product. When materials are held for an extended period of time, the expectation is that stability studies will be conduct to support the extended hold times. Reprocessing - requires that written procedure be established prescribing a system for reprocessing batches. Reprocessed batches must conform to established standards, specifications and characteristics. *next slide*
- Subpart G – Packaging and Label Control This subpart, again, is one that the FDA issues many findings of non-compliance for. Many of the non-compliances issues related to this subpart can result in a product being recalled. The sections of the subpart require that strict controls are in place to assure compliance with the regulations found here. *next slide*
- Subpart H – Holding and Distribution 211.142 Warehousing procedures - requires that all drug products be quarantined prior to release by the Quality Control unit and that all drug products are stored under appropriate conditions of temperature, humidity and light. 211.150 Distribution procedures - requires that the oldest approved stock of a drug product is distributed first. This is commonly known as FIFO (first in – first out). It also requires a system of identification of drug product that have been distributed to facilitate a recall if necessary. *next slide*
- Subpart I – Laboratory Controls This subpart covers specifications, standards, sampling plans, test procedures and other laboratory control mechanisms. Testing and release for distribution - requires that drug products have specifications for tests, including tests for identity and strength of each active ingredient. As well as testing to demonstrate the drug product is free from objectionable microorganisms. Stability testing - is required to establish expiry and storage conditions of drug products. Reserve samples - requires that 2X the amount of material required for full testing be retained for the active ingredient and drug product. *next slide*
- Subpart J – Records and Reports This subpart covers in detail the various records and reports required by the FDA for the manufacture of finished pharmaceuticals. The General Requirements section covers document retention, maintenance and storage. The documents covered by this subpart must be readily available, at the site where they were created, to the FDA upon a site inspection. Production record review - section requires that all production related documents be reviewed and approved by the Quality Control unit for compliance prior to a batch being released. Complaint files - section requires strict documentation of complaints received and an assessment of the complaint to determine whether the complaint represents a serious and unexpected adverse drug experience, which is required to be reported to the FDA. *next slide*
- Subpart K – Returned and Salvaged Drug Products Returned drug products - this section covers drug products that are returned to the manufacture for any number of reasons. It is necessary to identify these returns appropriately. Drug products must be destroyed if there is any evidence or doubts to the safety, identity, strength, quality or purity of the drug product. The section also allow for reprocessing of a returned product, providing the subsequent drug product meets appropriate standards, specification and characteristics. Drug product salvaging - is specific to drug products that have been exposed to improper storage conditions due to natural disasters, fires, accidents or equipment failures. Drug products may not be salvaged if there is evidence through testing that the identity, strength, quality and purity have been impacted and/or evidence that the drug product and associated packaging were subjected to improper storage as a result of the disaster or accident. *next slide*
- I’ve brought us back to the FDA’s website page for the Code of Federal Regulations because I would like to emphasize the importance of the ‘FDA Guidance Documents’ *click* Found on the right column under ‘Other databases’. *next slide*
- This page allows you to search the 3,441 FDA Guidance documents in this database. The documents found here are must when it comes to understanding the expectations the FDA has for compliance. However, they are not legally binding. The FDA does allows for alternative approaches as long as the approach satisfies the requirements of the regulation. *next slide*
- We’ve reached 1990 and the importance of a global community.
- The International Council for Harmonization, better known as ICH came about as there was a recognized need for global harmonization on such topics as Safety, Quality and Efficacy. The European Community initiated discussions with the U.S. and Japan in the 1980s but it wasn’t until 1990 that the ICH was officially established. The link I have provided here will bring you to the ICH homepage. *next slide*
- The ICH homepage has many areas containing useful information *click* but I would like to focus on the ‘Work Products’ tab highlighted in red in the menu bar at the top of the page. It is here, under ‘ICH Guidelines’ that you will find a link to the ‘Quality Guidelines’. You may also access this information through the ‘Q’ link at the top of the page or the ICH Guideline Database link, both, also highlighted in red. *next slide*
- The ICH Quality Guidelines are broken down into 14 sections as listed here. You need to consider the scope of each of these documents when referencing them. For instance, Q7 – Good Manufacturing Practice is for the manufacture of active pharmaceutical ingredients not for Finished Pharmaceuticals as required by Part 211. However, Q1 Stability, Q2 Analytical Validation, Q3 Impurities, Q4 Pharmacopeias, Q6 Specifications, Q8 Pharmaceutical Development, Q9 Quality Risk Management, Q10 Pharmaceutical Quality System, Q12 Lifecycle Management Q13 Continuous Manufacturing of Drug Substances Drug Products and Q14 Analytical Procedure Development are directly applicable to 21 CFR Part 211. The links on this page will provide you with downloadable .pdf copies of the guidelines. And again, I would recommend that you take some time to look through them in order to better understand the expectations the FDA has for compliance. *next slide*
- This bring me to my final slide. I’ve provided some Tips to keep in mind when working with the CFR - Pharmaceutical regulations and guidance documents are a collaborative effort in today’s global industry. Part 210 and 211 describes the WHAT you must do for regulatory compliance. In order to find the HOW to be compliant, look for industry guidance documents and information provided by the FDA and other organizations that are recognized by the FDA. I have also provided links to organizations that assist the FDA in providing knowledge and guidance to help better understand FDA expectations.