A Fun and Brief Analysis of Part 211 Current Good Manufacturing Regulations: Shall(s) versus Warning Letters

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A Fun and Brief Analysis of Part 211 Current Good Manufacturing Regulations: Shall(s) versus Warning Letters

Objective:

To practice LaTeX, study the 21 Code of Federal Regulations Part 210, Current Good Manufacturing Practice in Manufacturing, Processing, Packaging, or holding of drugs; General and Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, and perform a fun little risk analysis evaluation to facilitate my studying. Can one use 'shall' bias as a prediction of a Food and Drug Administration Investigator's inspectional focus?

Scope

Is there a correlation between the number of 'shall(s)' in 21 Code of Federal Regulations Sections and the number of times those sections are mentioned in a Food and Drug Administration Warning Letters? As we all know, there is a difference between shall and should. In fact, a shall in the regulations is a written order, and should is used in Guidance Documents as a suggestive term. In other words, will the US FDA investigator's thought process or software be biased towards 21 Code of Federal Regulation Sections that have a greater number of mentioned 'shall(s)'. In truth, I am doing a very basic risk analysis of Part 211 Current Good Manufacturing of Finished Pharmaceuticals.

With that said, I realize all regulations are important, and, for that reason, I read and study all the regulations, but It is nice to "sample" the warning letters, look up the mentioned subparts and sections, and compare the thoughts of FDA Investigators with the regulations. For me, it puts things into perspective. I would NOT use such a risk analysis as a means to prepare a report or prepare for an investigation because violation of any section leads to an adulterated product. In that sense, they are all important. Still, the analysis was interesting and I plan to add to the data as I read more Warning Letters.

Method

First, I read 21 Code of Federal Regulations, Part 210, Current Good Manufacturing Practice in Manufacturing Processing, Packaging, or Holding of Drugs; General, and Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals. After two readings, I navigated to the United States Food and Drug Administration website 'FDA's' Electronic Reading Room - Warning Letters, Browse Warning Letters by Subject, where I selected the following 'group(s)':

• CGMP for Drugs/Manufacture, Processing, Packaging, Holding/ Adulterated/Misbranded,

• CGMP for Finished Pharmaceuticals,

• CGMP for Finished Pharmaceutical/Adulterated,

• CGMP for Finished Pharmaceuticals/Adulterated,

• CGMP for Finished Pharmaceuticals/Deviations/Adulterated

• CGMP for Finished Pharmaceuticals/Drug and Cosmetic Manufacturing Facility/Adulterated,

• CGMP for Finished Pharmaceuticals/Human Drug Manufacturing Manufacturing Facility/Adulterated,

• CGMP for Finished Pharmaceuticals/Misbranded/Adulterated,

• CGMP for Finished Pharmaceuticals/OTC Drug & Dietary Supplement/Adulterated,

• CGMP for Finished Pharmaceuticals/Postmarketing Adverse Drug Experience/Adulterated.

After selecting a group, I decided to read all warning letters within the group, but, as time progressed, I read all if the number was two and below because I wanted to place the data online. If greater than two, I used MicroSoft Excel 'RandBetween' to choose two from a group greater than two. During my analysis, I evaluated a total of 17 Warning Letters. As I mentioned previously, I will read more warning letters and add data over time.

Next, I returned to the 21 Code of Federal Regulations, Part 211, Current good Manufacturing Practice for Finished Pharmaceuticals, and I counted the number of 'shall(s)'. Since I wanted a ratio of shall/paragraph for my own comparison, I decided that a paragraph was labeled between a to z. Next, I counted the shall(s) but I also counted each subparagraph as a shall if shall applied to that subparagraph. As an example, I will use 21 Code of Federal Regulations; Part 211; Subpart C, Buildings and Facilities; Section 211.42, Design and construction features.

There are four paragraphs: a thru d. Paragraph a has 1 shall; paragraph b has 2 shall(s); paragraph c has 2 shall(s) but each applies to all subparagraphs, so I assigned a shall to each subparagraph. Since there are 16 subparagraphs and 2 shall(s), the total for c is 18 shall(s); and paragraph d has 1 shall. The total number of shall(s) for Section 211.42, Design and construction features, were 22. Once I had the method, I prepared an Excel workbook to collect data for future analysis. As I read 21 Code of Federal Regulations, Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, I counted and recorded the number of 'shall(s)' per section. I also recorded the number of a to z paragraphs.

Afterwards, I returned to the above mentioned Warning Letter 'groups', read warning letters, and recorded a section each time it was mentioned. As I recorded and read 17 warning letters, I also opened an internet navigator and read the respective 21 Code of Federal Regulation Subpart and Section as well.

Results

Shall Language and Data:

The important legal term of shall was emphasized often in the 21 Code of Federal Regulations, Part 211, Current Good Manufacturing Practices for Finished Pharmaceuticals.

 

In Figure 1, Subpart E, Control of Components and Drug Product Containers and Closures, Section 211.84, Testing and approval or rejection of components, drug product containers, and closures, has the most 'shall(s)' at 25, and several Sections have the minimum value of 1. Although Subpart A, General Provisions, Section 211.3, Definitions, has a value of 0, I excluded it as a minimum because it refers to the definition section of Part 210, Current Good Manufacturing Practice in Manufacturing, Processing, Packaging, or Holding of Drugs; General, Section 210.3, Definitions. Section 211.42, Design and construction features, follows as the next maximum at 22 shall(s). The third, forth, and fifth maximums are Subpart I, Laboratory Controls, Section 211.170, Reserve Samples; Subpart J Records and Reports, Section 211.194, Laboratory records; and Subpart I Laboratory Controls, Section 211.160, General requirements, at 19 shall(s), 19 shall(s), and 18 shall(s), respectfully.

Normalization was applied by using the average value of shall emphasis. After normalization with an average value of 7, the number of Sections above or equal to 7 are 24 out of 60 Sections.

Figure two is interesting because a rising trend occurs in the Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals. There are more Sections, 16, above the average value of 7 after Subpart E, Control of Components and Drug Product Containers and Closures, Section 211.105 when compared to number of Sections, 5, above and prior to the same Subpart and Section. The Subparts after Section 105: Subpart F, Production and Process Controls, Sections 211.110 to 211.115; Subpart G, Packaging and Labeling Control, Sections 211.122 to 211.137; Subpart H, Holding and Distribution, Sections 211.142 and 211.150; Subpart I, Laboratory Controls, Sections 211.160 to 211.176; Subpart J, Records and Reports, Sections 211.180 to 211.198; and Subpart K, Returned and Salvaged Drug Products, Section 211.201 to 211.208. When evaluating the percentage above the average value of 7, it is discovered that the values are: 25% Subpart F, Production and Process Controls, Sections 211.100 to 211.115; 67% Subpart G, Packaging and Labeling Control, Sections 211.122 to 211.137; 0% Subpart H, Holding and Distribution, Sections 211.142 and 211.150; 71% Subpart I, Laboratory Controls, Sections 211.160 to 211.176; 67% Subpart J, Records and Reports, Sections 211.180 to 211.198; and 0% Subpart K, Returned and Salvaged Drug Products, Sections 211.204 and 211.208.

From the latter shall language and data, Subpart I, Laboratory Controls, Sections 211.160 to 211.176, is the 'most' risky group and it also has two sections, Section 211.160, General Requirements, and Section 211.170, Reserve Samples, that appear as 'most' risky sections. As previously mentioned, Subpart E, Control of Component and Drug Product Containers and Closures, Section 211.84, Testing and approval or rejection of components, drug product containers, and closures and Subpart C, Buildings and Facilities, Section 211.42, Design and construction features, are the 'most' risky Sections.

Appearance of 21 CFR Sections in Warning Letters:

The FDA provide Warning Letters as a means to inform a manufacture of violations that need attention. If the manufacture does not remediate the Code of Federal Regulations violations, it will be, according to the law, producing product that violates the FD&C Act. As such, the FDA could seek a Consent Decree and seize the products. A warning letter is issued after a series of checks and balances. First, one or more investigators perform an inspection and record CFR deviations. Next, the investigator's supervisors review the deviations, analyze the language, and submit the information to compliance. Compliance reviews the deviations, consults with appropriate third party persons, and prepares and sends a letter to the manufacture. The warning letter mentions which Sections of the CFR have been violated.

In my analysis, I read 17 warning letters and recorded which Sections of 21 Code of Federal Regulations, Part 211, Current Good Manufacturing Practices for Finished Pharmaceuticals was mentioned. As the reader will notice, not all sections of 21 CFR are mentioned. In fact, only 28 of the 60 Sections were mentioned in the 17 Warning Letters.

 

The greatest value, 13, in Figure 3 is Subpart B Organization and Personnel, Section 211.22, Responsibilities of quality control unit. The next maximum value is 9 and there are three Subparts and Sections: Subpart C, Buildings and Facilities, Section 211.42, Design and construction features; Subpart F, Production and Process Controls, Section 211.100, Written procedures and deviations; Subpart I, Laboratory Controls, Section 211.165, Testing and release for distribution.

After normalizing the warning letters data by the average of 4, a similar analysis can be applied.

There are 10 Sections that were mentioned, on average, more often than 18 Sections that are less than the average of 4. As mentioned previously, not all the Sections appeared in the 17 Warning Letters. Therefore, not all the SubParts are going to be complete. The following Subparts and Sections are above the average value of 4: Subpart B, Section 211.22, Responsibilities of quality control unit; Subpart C, Buildings and Facilities, Section 211.42, Design and construction features; Subpart D, Equipment, Section 211.67, Equipment, cleaning, and maintenance; Subpart E, Control of Components and Drug Product Containers and Closures, Section 211.84, Testing and approval or rejection of components, drug product containers, and closures; Subpart F, Production and Process Controls, Section 211.100, Written procedures;deviations; Subpart F, Production and Process Controls, Section 211.113, Control of microbiological contamination; Subpart I, Laboratory Controls, Section 211.160, General requirements; Subpart I, Laboratory Controls, Section 211.165, Testing and release for distribution; Subpart I, Laboratory Controls, Section 211.166, Stability testing; and Subpart J, Records and Reports, Section 211.192, Production record review.

An interesting switch between the 'shall' analysis and the Warning Letter analysis occurs with Section 211.22, Responsibilities of quality control unit, of Subpart B, Organization and Personnel, Section 211.165, Testing and release for distribution, of Subpart I, Laboratory Controls, and Section 211.198, Complaint files of Subpart J. In truth, the switch of Section 211.22 is more interesting when considering the limited amount of available data, and the Subpart of Laboratory Controls appears significant in the 'shall' analysis and Warning Letter analysis. The two subparts are closely related since quality control is responsible for laboratory controls and other sections. Therefore, one can expect an intra-subpart interaction. As for Subpart J, Records and Reports, Section 211.198, Complaint files, there is a connection to the quality control unit but the Section is quite specific. As such, one may see a rise in data as more Warning Letters are read. Interestingly, the section also has extensive mentioning of expiration dating, and there are other sections more specific to expiration-Subpart G, Packaging and Labeling Control, Section 211.137, Expirations dating. Although below the average, the latter was mentioned 3 times in 17 warning letters. As a final analysis, I will overlay the available Warning Letter Sections with their respective shall Sections.

An Overlay Comparison: Number of 'shall' mentioning in Sections versus number of times a Section appears in Warning Letters:

The following graph is used to see if 'shall' may affect the outcome of 21 CFR Section prevalence in Warning Letters. In other words, an investigator may be biased by the word 'shall', which, in truth, makes sense. If there is a correlation, there should be some overlap. As mentioned before, there is not enough data to perform an actual statistical evaluation, and I would have to speak with a trained statistician about the most appropriate method. Instead, these comparisons are similar to the simple, yet effective, Pareto analysis that is often used prior to more sophisticated statistical analysis.

Since I have read the Warning Letters, my analysis is biased, but I believe another could obtain the same conclusion by looking at the data and then the language of 21 Code of Federal Regulations Part 211, Current Good Manufacturing Practices for Finished Pharmaceuticals.

First, why is Section 211.22 significant in Warning Letters but not so significant, when compared to the average, during 'shall' analysis? Section 211.22 is apart of Subpart B, Organization and Personnel, and is titled Responsibilities of the quality control unit. As we know, quality control is quite important. Another area that appears to be important is Laboratory Controls. According to past analysis, 71%, which was the greatest percentage of the analysis, of Subpart I, Laboratory Controls, had Sections above the 'shall' average of 7. When considering the number of times a section appeared in warning letters, there were 10 of 28 sections above the average of 4. Of those 10, three Subpart I, Laboratory Controls, Sections appeared. After reviewing Section 211.22, Responsibilities of quality control unit, and other Sections, there is definitely a intra-section relationship to the Quality Control Unit.

As a check, I searched 21 Code of Federal Regulations for 'quality control', and discovered the following following sections:

• 211.22, Responsibilities of quality control unit; 211.42, Design and construction features; 211.84, Testing and approval of rejection of components, drug product containers, and closures; 211.87, Retesting of approved components, drug product containers, and closures; 211.100, Written procedures;deviations; 211.101, Charge-in of components; 211.110, Sampling and testing of in-process materials and drug products; 211.115, Reprocessing; 211.142, Warehousing procedures; 211.160, General requirements; 211.165, Testing and release for distribution; 211.192, Production record review; and 211.198, Complaint files.

As one can see, many of the significant Sections can be found in the above bulleted paragraph.

Conclusion:

Although all parts of 21 Code of Federal Regulations and their corresponding subsections are important, there appears to be a relationship between 'shall' language and warning letters, but the FDA Investigator decision is more complicated than 'shall' language. The most substantial relationship appears to be related to sections that mention quality control as well. The latter makes sense because the 'test method' is the foundation for a successful validation program, which leads to a consistent quality product. The latter is the reason the FDA demands that a quality control unit be created-Subpart B, Organization and Personnel, Section 211.22, Responsibilities of quality control unit. If quality procedures are outsourced, the outsourced activity must be verified as well. The latter is why Section 211.22 became significant during the Warning Letter analysis. The quality unit is the foundation for a quality product. As such, many sections can be connected to Section 211.22, and FDA personnel are trained to place as many connected 21 CFR Subparts and sections as possible when writing a FDA 483.

From my simple analysis, I believe one can argue that 'shall' bias does have an impact because there are Sections that were seen throughout the analysis. In addition, the analysis showed why one should not use such an analysis to concentrate on individual sections when operating or preparing for an investigation. New knowledge was discovered as well. The importance of Section 211.22, Responsibilities of the quality control unit, was discovered and then verified by a simple search. The search revealed which sections mentioned 'quality control', and many of those sections were significant during the analysis. Therefore, one can argue that attention to 'shall' and 'quality control' are important!

References:

1. United States Food and Drug Administration. CFR - Code of Federal Regulations Title 21. US FDA[online]. 2011. Available from: Search

2. United States Food and Drug Administration. FDA's Electronic Reading Room - Warning Letters. US FDA[online]. 2011. Available from: List

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