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If your answer to any of the questions is 'Yes', you must consider manufacturing Pharmaceutical Intermediates. Why?
Because you need Pharmaceutical Intermediates to manufacture the Active Pharmaceutical Ingredients.
But why the Active Pharmaceutical Ingredients are Important?
Powerful Medicines
Just think about the Powerful Medicines which save you from Life-Threatening diseases.
Do you know why they’re so effective against the diseases?
They’re effective because their power comes from the active pharmaceutical ingredients. In fact, these powerful medications are formulated with active pharmaceutical ingredients. Because these active molecules actually fight with the diseases.
No doubt the medicines are essential to save us from dangerous diseases. But they must be manufactured at large scale in sufficient quantities at reasonable costs. Why?
Because all of us can’t take the advantage of them and it won’t serve any useful purpose unless they’re available at affordable prices.
And in order to make the medicines available at affordable prices, you need to manufacture high quality active pharmaceutical ingredient molecules at low costs. Why?
As we’ve mentioned earlier, active pharmaceutical ingredients make the medicines powerful. That’s why the availability and the cost of the medicines will depend on the availability and the cost of the active pharmaceutical ingredients. Isn’t it?
So the challenge is to make active pharmaceutical ingredients in sufficient quantities at low costs. Right?
When you get into the details of the manufacturing processes used in making active pharmaceutical ingredient molecules, you’ll find most of them involve chemical synthesis.
But when you think about synthesizing them, you find them to be challenging. Why?
It’s because the synthesis process involves multiple reaction steps along with complex reactions.
So how to make the manufacturing of active pharmaceutical ingredient molecules easy?
That’s where the pharmaceutical intermediates come into the picture.
Pharmaceutical Intermediates
In fact, when you talk about the multi-step synthesis, the manufacturing processes become complex and difficult. Why?
It’s because you need to start with the basic molecules – the chemical feedstock. Then you need to go through multiple synthesis steps to make the final active pharmaceutical ingredients molecule.
As we’ve mentioned earlier most of the synthesis processes are based on chemical reactions. But the issue is most of the active pharmaceutical ingredients manufacturers are reluctant to make the molecules from the basic stage. Why?
It’s because multi-step synthesis involve different types of unit processes and unit operations along with handling the intermediates of various synthetic stages. And you need to carry out multiple processes and use multiple process equipments. You will need specialized equipments especially for difficult synthesis processes.
If you get into the details of the synthesis processes used for making active pharmaceutical ingredients molecules, you’ll find that most of them are complex calling for expertise in many areas.
That’s precisely where the intermediate molecules become useful in manufacturing. The active pharmaceutical ingredients manufacturers procure the relevant intermediate molecules and make their product using one or two simple synthesis steps.
These intermediate molecules are nothing but Pharmaceutical Intermediates.
These Pharmaceutical Intermediates are classified into two categories:
Basic Pharmaceutical Intermediate
When you talk about the basic pharmaceutical intermediates, they’re relatively simple and made by using few synthesis steps from the basic chemical feed stock.
They can be used in two situations:
Especially when the manufacturers have the manufacturing facilities and expertise to handle multiple synthesis steps, making active pharmaceutical ingredients molecule makes business sense.
Advanced Pharmaceutical Intermediate
When you talk about the advanced pharmaceutical intermediate molecules, they’re are structurally complex. That’s why they’re made by using multiple synthesis steps involving specialized unit processes and unit operations. Of course, they’re expensive. But they’ve got their own applications.
They can be used in two situations:
Most of the active pharmaceutical ingredient molecules sell at high prices. In that situation, when the manufacturers do the product costing, they find the cost contribution of the advanced pharmaceutical intermediates is not significant. That’s why they’re ready to pay for these molecules rather than manufacturing themselves.
Why Pharmaceutical Intermediates?
Now, let’s come to the main point. Does it make business sense to manufacture pharmaceutical intermediates?
Because when you think as an entrepreneur, you’ll find that two things can make the difference between success and failure of any business.
Let’s list then down:
First of all, let’s get into the details of the market prospects…
Good Market Prospects
When you talk about the market prospects of pharmaceutical intermediates, it depends on the market for the active pharmaceutical ingredients. When it comes to the market of active pharmaceutical ingredients, it’s growing at a fast pace.
Of course, the reasons are many. Let’s talk about some of them:
The increased consumption of medicines have made the demand for active pharmaceutical ingredients very high. As the demand of pharmaceutical intermediates is directly linked with the demand of active pharmaceutical ingredients, there’s good market prospects for them.
Now, it’s time to talk about the business profitability.
The Business must be Profitable
Today, the profitability of manufacturing pharmaceutical intermediates is very high.
And it’s because of multiple factors:
So, it’s an incredible business opportunity. Isn’t it? The important question here is how to utilize the opportunity to the fullest.
But before getting ahead further, let’s see how the pharmaceutical intermediates molecules are manufactured.
Manufacturing Process
As we’ve discussed earlier. the manufacturing processes involve multiple unit processes and unit operations to convert the raw materials into the finished products. And most of the times the raw material molecules are changed to make new molecules.
When you study the manufacturing processes of pharmaceutical intermediates molecules, you’ll find four different types:
But most of the manufacturing processes of pharmaceutical intermediates molecules, involve chemical synthesis.
Option for Chemical Manufacturers
As we’ve discussed earlier, today manufacturing pharmaceutical intermediates has emerged as a profitable option especially for the leading chemicals manufacturers. Why?
There’re various reasons. However, we shall discuss about a few of them:
Expertise in Unit Processes and Unit Operations
As a chemical manufacturer, you have already developed expertise in difficult unit processes as well as unit operations. In fact, the pharmaceutical intermediates are chemical products.
So why not take the advantages of your expertise in manufacturing the pharmaceutical intermediates? In fact, you can make them more efficiently.
Safety and Environment Systems
Since you’re involved in chemical manufacturing, the safety and environment systems are in place. And you’ve already optimized them. The manufacturing processes of most of the pharmaceutical intermediates generate wastes.
So why not utilize your expertise in environmental management? In fact you’re in a better position to handle the waste streams and make use of the byproducts and coproducts optimally.
Of course, you can take the advantages of integrated manufacturing by Process Integration as well as Energy Integration.
Selecting Pharmaceutical Intermediates
When you talk about pharmaceutical intermediates manufacturing, selecting the right molecules is the starting point. But it’s the most important aspect of your manufacturing business. Why?
Because most of the critical aspects of your business gets decided once you finalize the molecules to manufacture. In fact, it can make the difference between success and failure.
But how to select the right pharmaceutical intermediate molecules?
Especially when it comes to the chemical manufacturers, the selection becomes more important. Because you’re not starting from the scratch. You have already chemical manufacturing facilities and experience in making chemical products.
That’s why you must utilize the resources available to you optimally.
Let’s come back to what we were discussing – product selection. In fact, the product selection is challenging. Why? Because looking to the dynamic business environment, in order to select the right molecule, you need to go for detailed analysis of the technical and commercial aspects.
Let’s talk about some important techno-commercial aspects.
In fact, in any manufacturing business product applications are of utmost importance.
When it comes to the pharmaceutical intermediates, they’re used as key starting materials for manufacturing active pharmaceutical ingredients. But they don’t have any direct use. Because they’re never used directly in formulating pharmaceutical products. That’s why the product quality must meet the requirements of the active pharmaceutical ingredient manufacturers.
Medication Categories
As we’ve mention earlier, the market demand for effective medication is going up day by day. So the market demand for active pharmaceutical ingredients are increasing very fast.
And different active pharmaceutical ingredients cater to different medication categories. You can consider them for evaluating the pharmaceutical intermediates molecules to manufacture.
Some of the medication categories are mentioned below:
When you’ve the adequate information on the type of medicines used against the diseases, you can think of the which pharmaceutical intermediates are in demand.
It’ll help you a lot to estimate their markets. Of course, there are thousands of active pharmaceutical ingredients used against a wide number of diseases.
If you study the manufacturing processes of active pharmaceutical ingredients, you’ll find multiple pharmaceutical intermediates are used for a single molecule. So you can always select the right pharmaceutical intermediates for your manufacturing business and add value.
Of course, you must have detailed knowledge on the synthesis processes to evaluate the molecules thoroughly. But you have got choice. Isn’t it?
Though the things are difficult, it offers incredible opportunities especially innovation focused manufacturers. Why?
Because if you can identify the techno-commercial incongruences, you can develop great profit-making ideas and add massive value to your manufacturing business. But you must be knowledgeable about pharmaceutical ingredients manufacturing.
For that you need to study the manufacturing processes of hundreds of pharmaceutical ingredients. And you need to make massive efforts to collect techno-commercial information and evaluate them following an innovative and integrated approach. Why?
Because that’s essential to optimize the diverse business aspects and extract meaningful conclusion. But the outcome will surprise you. It’ll be easy for you to select extremely profitable pharmaceutical ingredients for manufacturing.
Let’s Conclude
The best way to get associated with the High Potential Fast Growing Pharmaceutical Industry is to manufacture Pharmaceutical Intermediates. Why?
Because it’ll help you not only to achieve Business Success but also to Contribute to the Society significantly. The modern world can’t sustain without Medications.
As an Entrepreneur, it’s important for you to make the Medicines available at affordable prices, by manufacturing high quality Pharmaceutical Intermediates at low costs. Why?
Because you need Pharmaceutical Intermediates to manufacture the Active Pharmaceutical Ingredients which are the Active Components of the Powerful Medications and actually fight with the diseases.
The Pharmaceutical Intermediates are classified into two categories:
From an entrepreneur’s perspective manufacturing Pharmaceutical Intermediates makes business sense because of the Market and Business Profitability.
In order to be successful in Pharmaceutical Intermediates Manufacturing, you must Select the Right Molecule and the Process Technology to manufacture them Profitably and Sustainably.
But it’s quite challenging. You need to consider many conflicting techno-commercial aspects in order to arrive at the best possible solutions. In fact, you need to follow an innovative approach based on integrated optimization.
That's where the Process industry innovations comes into the picture.
Process industry innovations are powerful enough to achieve the desired improvements.
Once you implement the innovation initiatives in your Pharmaceutical Intermediates Manufacturing Business, you yourself will be convinced that it works.
Let’s join hands in using Process industry innovations and developing them further in order to make the Manufacturing Business Profitable and Sustainable.
Perhaps you can consider taking the help of Industry Experts to make the process fast and effective.
What is your experience in Manufacturing Pharmaceutical Intermediates?
Contains Nonbinding Recommendations
1. Do the CGMP regulations require a firm to retain the equipment status identification labels with the batch record or other file? Assuming each major piece of equipment has a unique cleaning and use log that is adequately retained, is it acceptable to discard these quick reference equipment labels?
The CGMP regulations for finished pharmaceuticals require the retention of cleaning and use logs for non-dedicated equipment, but no similar requirement exists for retaining what are intended to be quick reference or temporary status labels. Examples of these kinds of status labels include mixing lot ###; clean, ready for use as of d/m/y; and not clean. We see no value in the retention of such labels in addition to the required equipment log or batch record documentation. The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process. Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment. The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for nondedicated equipment.
Labels are merely one way to display temporary status information about a piece of equipment. It is considered acceptable practice to display temporary equipment status information on dry-erase boards or chalkboards. And it would be appropriate for an FDA investigator to verify that the information on a temporary status label is consistent with the log.
References:
2. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?
Yes. Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container or closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMP requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For containers or closures purporting to be sterile or depyrogenated, sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 21 CFR 211.94 and 211.113(b)). This is to preserve the fitness for use of the remaining containers or closures as well as to ensure sample integrity, if they are to be examined for microbial contamination. At a minimum, any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i.e., wiping outside surfaces, limiting time that the original package is open, and properly resealing the original package). Well-written and followed procedures are the critical elements.
Note that the CGMP regulations at 21 CFR 211.84 permit a manufacturer to release for use a shipment of containers or closures based on the supplier's certificate of analysis and a visual identification of the containers or closures. Once a supplier's reliability has been established by validation of their test results, a manufacturer could perform the visual examination entirely in the warehouse.
References:
3. A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through a 0.2 micron sterilizing filter. Investigation did not show any obvious causes. What could be the source of contamination?
A firm had multiple media fill failures. The media fill runs, simulating the filling process during production, were conducted inside an isolator. The firm used TSB (nonsterile bulk powder) from a commercial source and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An investigation was launched to trace the source of contamination. The investigation was not successful in isolating or recovering the contaminating organism using conventional microbiological techniques, including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media, and examination under a microscope. The contaminant was eventually identified to be Acholeplasma laidlawii by using 16S rRNA gene sequence. The firm subsequently conducted studies to confirm the presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the process, but from the media source.
Acholeplasma laidlawii belongs to an order of Mycoplasma. Mycoplasma contain only a cell membrane and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain. Individual organisms are pleomorphic (assume various shapes from cocci to rods to filaments), varying in size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is capable of penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, Eisenhuth, et al. 1999). Acholeplasma laidlawii is known to be associated with animal-derived material, and microbiological media is often from animal sources. Environmental monitoring of Mycoplasma requires selective media (PPLO broth or agar).
Resolution:
For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter (note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation). In the future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier. (Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.) The firm will continue monitoring for Mycoplasma and has revalidated their cleaning procedure to verify its removal. In this case, a thorough investigation by the firm led to a determination of the cause of the failure and an appropriate corrective action.
References:
Date: 5/18/2005
4. Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes. Is this okay?
Maybe. It depends on the cause and consistency of the reject rate. Many transdermal patch manufacturing processes produce more waste (i.e., lower yield from theoretical) than other pharmaceutical processes. This should not of itself be a concern. The waste is usually due to the cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps higher rates of in-process sampling. This is most pronounced for processes involving lamination of rolls of various component layers. Roll-stock defects detected during adhesive coating of the roll, for example, can often only be rejected from the roll after final fabrication/lamination of the entire patch, which contributes to the final process waste stream.
We expect that validated and well-controlled processes will achieve fairly consistent waste amounts batch-to-batch. Waste in excess of the normal operating rates may need (see 21 CFR 21.192) to be evaluated to determine cause (e.g., due to increase in sampling or higher than normal component defects...or both) and the consequences on product quality assessed. We've seen a small number of cases where unusually high intra-batch rejects/losses were due to excessive component quality variability and poorly developed processes.
References:
21 CFR 211.100: Written procedures; deviations
21 CFR 211.103: Calculation of yield
21 CFR 211.110: Sampling and testing of in-process materials and drug products
21 CFR 211.192: Production record review
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5. Does CGMP regulations require three successful process validation batches before a new active pharmaceutical ingredient (API) or a finished drug product is released for distribution?
No. Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process. The current FDA guidance on APIs (see guidance for industry ICH Q7 for APIs) also does not specify a specific number of batches for process validation.
FDA recognizes that validating a manufacturing process, or a change to a process, cannot be reduced to so simplistic a formula as the completion of three successful full-scale batches. The Agency acknowledges that the idea of three validation batches became prevalent in part because of language used in past Agency guidance. FDA's process validation guidance now recommends a product lifecycle approach. The emphasis for demonstrating validated processes is placed on the manufacturer’s process design and development studies in addition to its demonstration of reproducibility at scale, a goal that has always been expected.
However, a minimum number of conformance (a.k.a. validation) batches necessary to validate the manufacturing processes is not specified. The manufacturer is expected to have a sound rationale for its choices in this regard. The Agency encourages the use of science-based approaches to process validation.
In March 2004, FDA revised the Compliance Policy Guide (CPG) Sec. 490.100 on Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. The CPG describes the concept that, after having identified and establishing control of all critical sources of variability, conformance batches are prepared to demonstrate that under normal conditions and operating parameters, the process results in the production of an acceptable product. Successful completion of the initial conformance batches would normally be expected before commercial distribution begins, but some possible exceptions are described in the CPG. For example, although the CPG does not specifically mention concurrent validation for an API in short supply, the Agency would consider the use of concurrent validation when it is necessary to address a true short-supply situation, and if the concurrent validation study conforms to the conditions identified in the CPG (see paragraph 4, a-c).
The conditions outlined in the CPG include expanded testing for each batch intended to address a short-supply situation. Expanded testing conducted according to an established validation protocol could provide added assurance that the batch meets all established and appropriate criteria before the API is used in the finished drug product. Additionally, confidence in the API manufacturing process may be gained by enhanced sampling (larger sample size representative of the batch) and perhaps the testing of additional attributes. Validated analytical methods are needed for testing every batch, including validation batches. The Agency would also expect the manufacturer to use a validation protocol that includes a review and final report after multiple batches are completed, even though the earlier batches may have been distributed or used in the finished drug product.
References:
6. Is it generally acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying its facility?
No. It is generally not acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO [International Organization for Standardization] 14644-1 Part 1: Classification of Air Cleanliness (14644-1) and ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 (14644-2) when qualifying its facility. Rather, a manufacturer of sterile drug products produced by aseptic processing should use these ISO standards in combination with applicable FDA regulations, guidance, and other relevant references to ensure a pharmaceutical facility is under an appropriate state of control. Consequently, appropriate measures augmenting ISO’s recommendations (e.g., with microbiological data) would likely be expected for a firm to meet or exceed CGMP in a pharmaceutical facility.
Please understand that 14644-1 and 14644-2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones (Federal Standard 209E). In November 2001, the U.S. General Services Administration canceled Federal Standard 209E.
Although 14644-1 and 14644-2 are not FDA regulations or FDA guidance, the Agency believes that they are useful in facilitating the international harmonization of industrial air classification for nonviable particle cleanliness in multiple industries (e.g., computer, aerospace, pharmaceutical). As such, FDA adopted these particle cleanliness ratings in the 2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice. However, due to the unique aspects of producing sterile drug products by aseptic processing (e.g., microbiological issues), an aseptic processing manufacturer should not rely solely on 14644-1 and 14644-2 when qualifying its facility.
References:
7. In 2004, FDA issued a guidance entitled PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance that encouraged industry to modernize manufacturing through enhancements in process control. How can I implement PAT (process analytical technology)?
The objective of FDA's PAT program is to facilitate adoption of PAT. In our 2004 guidance, we discuss FDA's collaborative approach to promote industry uptake of new and beneficial technologies that modernize manufacturing operations and enhance process control. FDA recognizes that firms should be encouraged to promptly implement new systems that improve assurance of quality and process efficiency. Accordingly, our approach to PAT implementation is risk based and includes multiple options:
(1) PAT can be implemented under the facility's own quality system. CGMP inspections by a PAT-certified investigator can precede or follow PAT implementation.
(2) As another quality system implementation option, FDA invites manufacturers to request a preoperational review of their PAT manufacturing facility and process (see ORA Field Management Directive No.135).
(3) A supplement (Changes Being Effected (CBE), CBE-30, or Prior Approval Supplement (PAS)) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT-certified investigator before implementation. This option should be used, for example, when an end product testing specification established in the application will be changed.
(4) A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies, and time lines. Following collaborative review of the general strategy outlined in the comparability protocol, the regulatory pathway can include implementation under the facility's own quality system, a preoperational review, CGMP inspections (either before or after PAT implementation), a combination of these, or another flexible approach.
Manufacturers should evaluate and discuss with the Agency the most appropriate option for PAT implementation (see questions 8 and 9, below).
References:
8. How do I contact CDER with questions about PAT?
Manufacturers should contact the Office of Pharmaceutical Quality and/or the appropriate review division in CDER to discuss applicability of PAT to CDER-regulated products.
Contact for further information:
CDER Key Officials
Date Revised: 6/18/2015
9. How do I contact CBER with questions about PAT?
Manufacturers should contact the appropriate review division in CBER to discuss applicability of PAT to CBER-regulated products.
Contact for further information:
CBER Key Staff Directory
Date Revised: 9/16/2013
10. What is the acceptable media fill frequency in relation to the number of shifts? Normally, media fills should be repeated twice per shift per line per year. Is the same frequency expected of a process conducted in an isolator?
A firm's justification for the frequency of media fills in relation to shifts should be risk based, depending on the type of operations and the media fill study design. For closed, highly automated systems run on multiple shifts, a firm with a rigorous media fill design may be justified to conduct a lower number of total media fill runs. Such a program can be appropriate provided that it still ensures performance of media fills for each aseptic processing line at least semiannually. The 2004 guidance for industry on Sterile Drug Products Produced by Aseptic Processing states that "[A]ctivities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification program." In addition, the EU Annex 1, Manufacture of Sterile Medicinal Products, states that "Normally, process simulation tests should be repeated twice a year per shift and process."
Certain modern manufacturing designs (isolators and closed vial filling) afford isolation of the aseptic process from microbiological contamination risks (e.g., operators and surrounding room environment) throughout processing. For such closed systems,1 if the design of the processing equipment is robust and the extent of manual manipulation in the manufacturing process is minimized, a firm can consider this information in determining its media fill validation approach. For example, it is expected that a conventional aseptic processing line that operates on two shifts be evaluated twice per year per shift and culminate in four media fills. However, for aseptic filling conducted in an isolator over two shifts, it may be justified to perform fewer than four media fill runs per year, while still evaluating the line semiannually to ensure a continued state of aseptic process control. This lower total number of media fill runs would be based on sound risk rationale and would be subject to reevaluation if contamination issues (e.g., product nonsterility, media fill failure, any problematic environmental trends) occur.
l This does not apply to RABS (restricted access barrier systems).
References:
Date: 12/3/2009
11. Why is FDA concerned about human topical antiseptic drug products?
FDA has identified several incidents of objectionable microbial contamination of topical antiseptic drug products (e.g., alcohol pads or swabs used to prepare the skin prior to an injection). Microbial contamination may be caused by substandard manufacturing practices, and the Agency is concerned about safety risks, such as from infection, associated with this contamination.
Date: 12/21/2011
12. What specific CGMP regulations might be useful to manufacturers of topical antiseptic drug products?
Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires all drugs to be manufactured in conformance with CGMP. The CGMP regulations in 21 CFR parts 210 and 211 for finished pharmaceuticals apply equally to over-the-counter (OTC) and prescription (Rx) drug products (see Compliance Policy Guide Sec. 450.100).
The CGMP regulations provide the minimum legal requirements for conducting reliable operations (see 21 CFR part 211). Some relevant CGMP regulations, with a brief description, are given below:
Manufacturing Design and Control: CGMP Requirements and Recommended Guidance for Manufacturers
Design manufacturing facilities
(§ 211.42) and processes (see below) to prevent microbial contamination:
For nonsterile drug products,
establish control procedures to monitor output and validate processes to include bioburden testing (§§ 211.110(a)(6)), 211.111) and establish and follow written procedures designed to prevent the introduction of objectionable microorganisms (§ 211.113(a)).
For sterile drug products,
establish and follow written procedures designed to prevent microbial contamination (§ 211.113(b)). See the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.
(§ 211.110(a))
.Implement and validate needed changes when deficient manufacturing steps, equipment, or raw materials may be adversely affecting process control.
See the guidance for industry Process Validation: General Principles and Practices.
Ensure that operating procedures
will consistently produce a quality product (§ 211.100).
Review and evaluate any deviations or discrepancies documented during manufacturing and testing to determine if a product lacks assurance of sterility (for sterile antiseptics) or may be contaminated with
objectionable microorganisms
(for nonsterile antiseptics).
Document and implement any corrective actions deriving from the evaluation (§ 211.192).
Ensure that all equipment,
including water systems, operates consistently and is clean, sanitary, and suitable for its intended use (§§ 211.63, 211.65, 211.67, and 211.68).
Establish and follow in-process bioburden testing
procedures to help monitor in-process control, including understanding the bioburden challenge to a final sterilization process (§ 211.110(a)(6)).
Components, In-Process Materials, Containers or Closures, and Finished Product Testing: CGMP Requirements for Manufacturers
Establish appropriate written testing standards/specifications and sampling plans
for components, in-process materials, containers or closures, and finished products (§ 211.160).
Establish procedures for testing
and approval or rejection of components, drug product containers, and closures (§ 211.80).
Test
each lot of a drug product component and container or closure, including those that may be vulnerable to microbiological contamination (§211.84)(d)(4-5), including applicator material (e.g., cotton pads) and water used as an ingredient in the product
.before a batch disposition decision is made.
Test each batch of a sterile product for sterility (§
211.167)
.
Test each batch of a non-sterile product to ensure absence of objectionable microorganisms (§
211.165(b))
.
Management
The CGMP regulations require that the management of a manufacturing facility maintains a well-functioning quality system, which includes an effective quality unit vested with the responsibilities and authorities required under CGMP (§ 211.22). See ICH guidances for industry Q9 Quality Risk Management and Q10 Pharmaceutical Quality System.
References:
Date: 12/21/2011
13. How can manufacturers assess and address the risk of microbiological contamination of topical antiseptics?
Because there are potentially many different root causes of product contamination by microorganisms, it is imperative that manufacturers perform a manufacturing risk assessment to understand manufacturing failure modes and implement prevention measures.
In addition, any risk assessment approach should be informed by an understanding of the microbial contamination vulnerabilities of the concerned product. For example, some product considerations for manufacturers include, but are not limited to:
Determine the types of microbes that might survive or thrive in your products. Provide additional controls and testing based on the output of the risk assessment to ensure product quality.
Ensure that your microbial recovery methods are capable of detecting the types of microbes that may affect product quality.
Evaluate risk of contamination from components, including during component production, storage, or due to the intrinsic risk from source materials. Consider all possible sources of microbial contamination, including the following:
Components or products stored in open bins can be at risk for contamination by spore-forming microbes, such as Bacillus cereus, as well as by Serratia species and other worrisome airborne microbes (see the FDA news release and Morbidity and Mortality Weekly Report, referenced below). Manufacturing areas exposed to windy or poor HVAC conditions may increase the potential for this environmental contamination risk.
Some materials, especially from natural sources, may have high or objectionable intrinsic bioburden.
Water quality can pose a significant risk, as most antiseptics include water as a key ingredient.
Contaminated purified water has been the root cause of multiple recalls of antiseptics, including instances of antiseptics contaminated with Burkholderia (previously Pseudomonas
) cepacia
, an opportunistic pathogen.Unsanitary practices or sources.
When manufacturing in areas with high humidity, molds can be of special concern.
References:
Date: 12/21/2011
14. Can Leptospira species penetrate sterilizing-grade filters? If so, what should manufacturers keep in mind in their ongoing lifecycle risk management efforts to ensure microbial control?
FDA is aware of a report of Leptospira licerasiae contamination in cell cultures (see Chen, Bergenvin, et al. 2012). There is no indication that this bacterium ultimately contaminated either the finished drug substance or drug product. This bacterium has been found to pass through 0.1 µm pore size rated sterilizing-grade membrane filters. While this specific species was the identified contaminant in this case, other Leptospira species also are capable of passing through 0.1 µm pore size rated filters (see Faine 1982). Compendial microbiological test methods typically used in association with upstream biotechnology and pharmaceutical production are not capable of detecting this type of bacteria. Whether this apparently rare contamination risk may be more widespread is unknown, and we are sharing this information so that manufacturers can consider whether this hazard may be relevant to their operations.
Leptospira are Gram-negative aerobic spirochetes that are flexible, highly motile, and spiral-shaped with internal flagella. The bacteria measure 1μm in diameter and 10-20 μm in length. Leptospira are obligate aerobes that use oxygen as the electron receptor and long-chain fatty acids as a major source of energy. While some of the Leptospira are harmless fresh-water saprophytes, other species are pathogenic and can cause leptosporosis, a significant disease in humans and animals (Ricaldi, Fouts, et al. 2012; Matthias, Ricaldi, et al. 2008; Bharti, Nally, et al. 2003). Based on current information, Leptospira contamination does not appear to occur frequently, and purification steps that follow cell culture in a typical biotechnology operation would be expected to prevent carryover to the finished drug substance. Testing of bulk drug substances produced in the reported cases did not detect the Leptospira species, and no evidence of deleterious effects on in-process product were observed in the known case study. However, we are providing this communication to alert manufacturers that these types of bacteria can potentially:
As a general principle, manufacturers should use sound risk management and be aware of unusual microbiota reported in the literature that may impact their manufacturing processes (e.g., cell culture biotechnology, conventional sterile drug manufacturing). Manufacturers should assess their operations, be aware of potential risks, and apply appropriate risk management based on an understanding of possible or emerging contamination risks (see section 18.3 in ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients). As appropriate, preventive measures should be implemented during the product and process lifecycle. To illustrate, if leptospiral contamination is considered possible, or has occurred, risk mitigation procedures and practices for this microorganism should include at least the following:
(1) Review of available published articles from the scientific literature and technical reports by related industry organizations that may provide further understanding on how to mitigate this contamination hazard.
(2) Use of molecular or nonconventional microbial monitoring methods at appropriate intervals to detect microbial flora that may exist in processing steps or in the immediate environment, but are not readily detected by current routine methods. Such expanded testing should be used to modify the strategy (e.g., timing, frequency, types of tests) of detection and control in the event of newly identified risk posed by the viable, but not easily cultured, microorganism.
Examples include: a. Use of specialized media such as Ellinghausen McCullough Johnson Harris (EMJH) medium (Ellinghausen and McCullough 1965) or other suitable media (Rule and Alexander 1986). It should be noted that these bacteria typically grow very slowly. b. Use of validated polymerase chain reaction (PCR) methods (e.g., as an investigative tool) for rapid screening and detection of spirochete bacteria. c. Consideration of special stain techniques or other means to identify the presence of Leptospira (Frank and Kohn 1973).
(3) Use of conventional approaches. Firms should continue to properly employ basic, standard microbiology laboratory practices to detect contamination. For example, the laboratory should ensure that microscopic examination is part of its routine cell culture process control program, as it provides an important means of detecting microbial contaminants that may not readily grow on conventional media.
(4) Implementing such quality risk-management measures into the initial design (i.e., preventive actions) and promptly implementing an appropriate corrective action plan in response to newly identified contamination sources, throughout the life cycle of the product.
References:
Date: 12/20/2012
15. FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment. What were the Agency’s major concerns with this guidance?
FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below. Section V (Exhibit/Validation Batch Powder Mix Homogeneity) recommended that at least 3 replicate samples be taken from at least 10 locations in the powder blender, but that only 1 of the 3 replicates be evaluated to assess powder blend uniformity. The Agency currently recommends that all replicate samples taken from various locations in the blender be evaluated to perform a statistically valid analysis. This analysis can demonstrate that variability attributable to sample location is not significant and that the powder blend is homogenous. Statistical tools are available to ascertain both the number of replicates and the number of sampling locations across the blender that should be analyzed to conduct a valid analysis. Section VII (Routine Manufacturing Batch Testing Methods) acceptance criteria designated to the Standard Criteria Method and the Marginal Criteria Method were based upon the limits published in the United States Pharmacopeia (USP) General Chapter <905> Uniformity of Dosage Units. However, the procedures and acceptance criteria in General Chapter <905> are not a statistical sampling plan and so the results of the procedures should not be extrapolated to larger populations. Therefore, because the procedure and acceptance criteria prescribed in section VII provided only limited statistical assurance that batches of drug products met appropriate specifications and statistical quality control criteria, FDA no longer supports their use for batch release. Currently, there are several standard statistical practices that, if used correctly, can help to ensure compliance with CGMP regulations, including 21 CFR 211.110, 21 CFR 211.160, and 21 CFR 211.165.
References:
Date: 8/6/2013
16. Why is FDA concerned about proper sampling of powder blends?
The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test (see 21 CFR 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110). Between- and within-location variability in the powder blend is a critical component of finished product quality and therefore should be evaluated. Drug product manufacturers need to use a science- and risk-based sampling approach to ensure (a) adequacy of blend mixing and (b) that sampling of the blend is done at a suitable juncture in the manufacturing process. The sampling and analysis needs to ensure that no differences exist between locations in a blend that could adversely affect finished product quality. Traditional sampling using a powder-thief may have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or other sampling errors. However, powder-thief sampling remains widely used and provides reliable results in many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of mixing (see, e.g., the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance). If a manufacturer proposes to use a thief sampling method, the reliability of the method should be evaluated as part of analytical methods development.
References:
Date: 8/6/2013
17. What are some recommended innovative approaches to ensuring adequacy of mixing of powder blends?
Innovative approaches to consider include, but are not limited to: (a) PAT real-time monitoring and feed-forward controlling of the powder blending process (see the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance) and (b) use of statistical process control tools to monitor the powder blending process and to maintain a state of control. When a manufacturer decides to implement PAT or other process-monitoring and control techniques for powder blend homogeneity assessment, its decision should be supported with appropriate data and rationale using a science- and risk-based approach. For example, the effective sample size of powder examined by PAT probes has to be estimated such that the scale of scrutiny of the PAT powder blending monitoring can be justified (Wu, Tawakkul, et al. 2009). The number of PAT probes and their locations also have to be justified. If a scientifically sound PAT monitoring and control strategy is established, it can facilitate the assessment of (a) variability across locations within the powder bed (El-Hagrasy, Morris, et al. 2001), (b) variability over time of one location, and (c) potential correlation between the powder sample and the unit dosage form.
References:
Date: 8/6/2013
18. What are the Agency’s recommendations regarding in-process stratified sampling of finished dosage units?
Stratified sampling is recommended to be used when the population is known to have several subdivisions (i.e., locations), which may give different results for the quality characteristics measured. The Agency expects that no significant differences should exist between in-process locations that could affect finished product quality. Between- and within-location variability is a critical component of finished product quality and therefore should be evaluated. Please refer to ASTM E2709 and ASTM E2810 for further guidance on establishing acceptance criteria for a stratified sampling plan. References:
Date: 8/6/2013
19. For a nonsterile compendial drug product that includes an antimicrobial preservative in its formulation, may I release and market lots of this drug product with initial out-of-specification total aerobic plate counts if these lots test within specification 2 weeks later?
No. 21 CFR 211.113(a) requires appropriate written procedures to be established and followed during manufacturing to prevent objectionable microorganisms in drug products not required to be sterile. Additionally, the second paragraph of USP General Chapter <51> Antimicrobial Effectiveness Testing reads: Antimicrobial preservatives should not be used as a substitute for good manufacturing practices, solely to reduce the viable microbial population of a nonsterile product, or control the presterilization bioburden of a multidose formulation during manufacturing. Drug manufacturers should not rely on antimicrobial preservatives to reduce initial out-of-specification plate counts to within-specification levels and then market the product. Section 211.165(f) mandates that drug products failing to meet established standards or specifications be rejected. The initial test results exhibiting out-of specification levels of microbes are not disqualified even if subsequent test results are within specifications. In such cases, FDA still expects the manufacturer to reject the drug product based on the initial results. It is also not acceptable for manufacturers to allow an inappropriately long time (e.g., weeks) to pass before testing the product, which might permit the preservative to reduce levels of microbes possibly introduced during manufacture and thus avoid out-of-specification test results. Finally, drug manufacturers should review their manufacturing process to determine procedures or equipment that might introduce contaminating microorganisms into the process or product.
References:
Date: 6/11/2015
20. Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does objectionable mean anyway?
Yes, CGMP regulations do require these written procedures. 21 CFR 211.113(a) specifies that appropriate written procedures be established and followed to prevent growth of objectionable microorganisms in drug products not required to be sterile. Even though a drug product is not sterile, a firm must follow written procedures that proactively prevent introduction and proliferation of objectionable microorganisms. 21 CFR 211.165(b) states that “[t]here shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms” before it is released for distribution. The meaning of the term objectionable needs to be evaluated on a case-by-case basis by each drug manufacturer. The primary meaning relates to microbial contaminants that, based on microbial species, numbers of organisms, dosage form, intended use, patient population, and route of administration, would adversely affect product safety. Microorganisms may be objectionable for several reasons; for example, they:
Establishing production time limits is an example of a control to prevent growth of objectionable microorganisms. Per 21 CFR 211.111, time limits for the completion of each phase of production, when appropriate, must be established and followed. For example, if a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to help prevent objectionable microbial buildup. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures (see FDA guidance, referenced below).
References:
Date: 6/11/2015
21. For drug products formulated with preservatives to inhibit microbial growth, is it necessary to test for preservatives as part of batch release and stability testing?
Yes. Two types of tests are generally used. Initially, firms perform antimicrobial preservative effectiveness testing to determine a minimally effective level of preservative. Once that level has been determined, firms may establish appropriate corresponding analytical test specifications. Firms may then apply the analytical tests for preservative content at batch release and throughout the shelf life of lots on stability.
References:
Date: 6/11/2015
22. Is parametric release an appropriate control strategy for sterile drug products that are not terminally sterilized?
No. Parametric release is only appropriate for terminally sterilized drug products. Although both terminally sterilized and aseptically processed drug product batches are required to meet the sterility test requirement (see 21 CFR 211.167(a)) before release to the market, there are inherent differences between the production of sterile drug products using terminal sterilization and aseptic processing.
Products that are terminally sterilized are rendered sterile in their final, sealed units by sterilizers. Discrete physical parameters (e.g., temperature, pressure, and time) are continuously measured and controlled with robust precision and accuracy during processing. Additionally, parametric release incorporates a sterilization load monitor that is integral to satisfying the requirement for a sterility test (see § 211.167(a)) by confirming that the load has been exposed to the prescribed physical conditions. This allows manufacturers to couple adherence to sterilization cycle parameters with a load monitor to determine thermal lethality, thereby directly confirming sterility and substituting for the sterility test.
In contrast, aseptic processes do not subject the final, sealed drug product to a sterilization cycle, and monitoring the sterility hazards to drugs manufactured throughout aseptic manufacturing operations relies on indirect measurements. Sterilization processes (e.g., filtration) for the drug occur before further manipulations that are performed in Class 100 (ISO 5) environments where transient events can present microbial contamination risks during the manufacturing process. Consequently, indirect measurements used in aseptic processing provide limited information to conclude whether a batch is sterile. Even contemporary aseptic operations conducted in closed RABS and isolators can experience sterility and media fill failures, despite the substantial robustness of these technologies over traditional cleanroom and open RABS operations. The sterility test is therefore an essential element to monitor the state of control of an aseptic operation, and it is the last step in a series of fundamental, required controls that collectively contribute to the minimum assurance that a given manufacturing operation produced a drug that meets its sterility claim. The sterility test also protects patients by potentially preventing the distribution of an aseptically processed drug product batch posing serious safety concerns that would not otherwise be readily detected.
All quality control tests, including the sterility test, have limitations. Although the sterility test may not exhaustively assess batch sterility, the sterility test is, nonetheless, a critical component of a comprehensive control strategy that is designed to prevent microbiological contamination of drug products purporting to be sterile (21 CFR 211.113(b)). Innovations in sterility testing (e.g., rapid microbiological methods, genotyping) and the integration of these innovations into manufacturing operations may further improve prompt operational feedback, which can result in significant batch release efficiencies while ensuring equivalent or better ability to detect nonsterility compared with the compendial method. FDA encourages the use of beneficial testing innovations in conjunction with advanced manufacturing technologies (e.g., robotic isolators) to enhance process design and improve both microbial detection and identification.
Date: 8/11/2023
Contact for further information:
CDER-OPQ-Inquiries@fda.hhs.gov
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