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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. ). 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/
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
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 , 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:
21 CFR 211.100: Written procedures; deviations
21 CFR 211.110: Sampling and testing of in-process materials and drug products
Compliance Policy Guide Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
FDA Guidance for Industry, , ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
FDA Guidance for Industry, , Process Validation: General Principles and Practices
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 -1 and ISO -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] -1 Part 1: Classification of Air Cleanliness (-1) and ISO -2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO -1 (-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 -1 and -2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones (Federal Standard 209E). In November , the U.S. General Services Administration canceled Federal Standard 209E.
Although -1 and -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 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 -1 and -2 when qualifying its facility.
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7. In , 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 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).
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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/
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/
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 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/
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/
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
Components, In-Process Materials, Containers or Closures, and Finished Product Testing: CGMP Requirements for Manufacturers
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.
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Date: 12/21/
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:
References:
Date: 12/21/
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. ). 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 ). 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. ; Matthias, Ricaldi, et al. ; Bharti, Nally, et al. ). 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 ) or other suitable media (Rule and Alexander ). 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 ).
(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/
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/
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/
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. ). 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. ), (b) variability over time of one location, and (c) potential correlation between the powder sample and the unit dosage form.
References:
Date: 8/6/
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 E and ASTM E for further guidance on establishing acceptance criteria for a stratified sampling plan. References:
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Date: 8/6/
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/
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/
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/
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/
23. Does FDA consider ophthalmic drug products1 to be adulterated when they are not manufactured under conditions that ensure sterility throughout their shelf life and, in the case of multidose products, that prevent harmful microbial contamination throughout their in-use period?
Product sterility is a critical quality attribute (CQA) for ophthalmic drug products.2 Recent cases of microbially contaminated ophthalmic drug products leading to serious injury and death, as well as recent recalls, highlight the importance of product sterility.3 Manufacturers of drug products, including sterile products offered or intended for ophthalmic use, must comply with CGMP requirements in 21 CFR parts 210 and 211. Failure to comply with these requirements will cause affected products to be deemed adulterated under section 501(a)(2)(B) of the FD&C Act.
Sterile drug products must meet specific CGMP requirements for personnel, buildings and facilities, materials, production and controls, and testing, as appropriate, to ensure product sterility at the time of manufacture and throughout the product’s shelf life. FDA has published guidance4 to provide clarity on how manufacturers can meet CGMP requirements in 21 CFR parts 210 and 211 when manufacturing sterile drug and biological ophthalmic products using aseptic processing. Some of the relevant regulations and guidance applicable to products for ophthalmic use are summarized below.
FDA assesses compliance with these and other applicable CGMP requirements through facility inspections under section 704(a)(1) of the FD&C Act, records requests under section 704(a)(4) of the FD&C Act, and other oversight tools. Manufacturers can find additional insight in the guidance for industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, which, although focused on application submission, includes information about the efficacy of sterilization processes.
1 As defined in guidance for industry Quality Considerations for Topical Ophthalmic Drug Products (December ).
2 See 21 CFR 200.50(a)(1).
3 See FDA’s alerts and warnings about eye drops at https://www.fda.gov/drugs/buying-using-medicine-safely/what-you-should-know-about-eye-drops.
4 See FDA’s guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.
5 This is consistent with USP General Chapter <771> Ophthalmic Products–Quality Tests.
6 Liquid ophthalmic products in multidose containers should contain one or more suitable and harmless substances that will inhibit the growth of microorganisms; see 21 CFR 200.50(b). See also USP General Chapter <51> Antimicrobial Effectiveness Testing.
7 USP General Chapter <51> Antimicrobial Effectiveness Testing.
References:
Date: 5/22/
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The pharmaceutical intermediates market is poised for steady growth over the next few years, with its value expected to increase significantly from USD 36.62 billion in to USD 57.03 billion by . This growth corresponds to a CAGR of 4.5%, reflecting a consistent expansion driven by rising demand in the pharmaceutical sector.
As the backbone of active pharmaceutical ingredient (API) production, pharmaceutical intermediates are essential in drug formulation and manufacturing, making their market trajectory closely tied to overall pharmaceutical industry trends. The increasing prevalence of chronic diseases, aging populations, and the growing need for effective medications globally are fundamental forces propelling the market forward.
Pharmaceutical Intermediates Industry Assessment
Attributes Key Insights Industry Size (E) USD 36.62 billion Industry Value (F) USD 57.03 billion CAGR ( to ) 4.5%The market growth is further stimulated by the ongoing advancements in pharmaceutical manufacturing processes and technologies. These advancements facilitate the efficient and large-scale production of intermediates, which helps reduce production costs and improve product quality. In particular, the rising focus on generic drug manufacturing has created strong demand for pharmaceutical intermediates, as generics rely heavily on these substances to produce affordable, effective medicines.
The ability to produce high-quality intermediates in large volumes is critical for supporting the supply chain of generics, which constitutes a substantial portion of the global pharmaceutical market. Moreover, continuous innovation in synthetic chemistry and process optimization enables manufacturers to meet regulatory standards while enhancing yield and reducing environmental impact.
Another driving factor contributing to the market's expansion is the growing investment in pharmaceutical research and development by both public and private sectors. With an increasing number of new drug candidates entering clinical trials, there is a corresponding surge in demand for specialized intermediates tailored to novel APIs.
Additionally, the globalization of pharmaceutical supply chains and the outsourcing of intermediate production to cost-effective regions support market growth by improving accessibility and affordability. Overall, the pharmaceutical intermediates market is expected to benefit from these multi-faceted drivers, ensuring a robust and dynamic landscape through .
Comparative analysis of fluctuations in compound annual growth rate (CAGR) for the global pharmaceutical intermediates market between and on six months basis is shown below. By this examination, major variations in the performance of these markets are brought to light, and also trends of revenue generation are captured hence offering stakeholders useful ideas on how to carry on with the market's growth path in any other given year.
January through June covers the first part of the year called half1 (H1), while half2 (H2) represents July to December
The table presents the expected CAGR for the global pharmaceutical intermediates market over several semi-annual periods spanning from to . In the first half (H1) of the decade from to , the business is predicted to surge at a CAGR of 5.5%, followed by a slightly slower growth rate of 5.1% in the second half (H2) of the same decade.
Particular Value CAGR H1 5.5% ( to ) H2 5.1% ( to ) H1 4.5% ( to ) H2 4.2% ( to )In the next period from H1 to H2 , the growth rate is projected to slightly decrease to 4.5% in the first half and 4.2% in the second half. This reflects a decrease of 70 BPS in the first half and 90 BPS in the second half.
The Pharmaceutical Intermediates Market, the segmentation includes product types such as chemical intermediates, bulk drug intermediates, and custom intermediates; categories comprising branded drug intermediates and generic drug intermediates; applications including analgesics, anti-inflammatory drugs, cardiovascular drugs, anti-diabetic drugs, antimicrobial drugs, anti-cancer drugs, and others (neurological disorders, respiratory diseases, gastrointestinal conditions, and dermatological therapies).
End users such as biotech and pharma companies, research laboratories, and CMOs/CROs; and regions covering North America, Latin America, East Asia, South Asia and Pacific, Western Europe, Eastern Europe, and Middle East and Africa.
The chemical intermediates segment is poised to lead the global pharmaceutical intermediates market, capturing a significant market share of approximately 58.5% in . This segment’s dominance can be attributed to its crucial role in the synthesis of active pharmaceutical ingredients (APIs), which are essential for the production of both branded and generic medications.
Chemical intermediates are highly favored due to their versatility, stability, and compatibility with a variety of synthesis routes, making them indispensable across a broad spectrum of pharmaceutical manufacturing processes. Their demand is further strengthened by the continuous growth of the generic drug industry, the rising prevalence of chronic diseases, and the global expansion of pharmaceutical production capacities.
The bulk drug intermediates segment is primarily driven by the escalating need for bulk APIs, especially those utilized in the preparation of critical therapeutic drugs like antibiotics, antiviral medications, and oncology treatments. Emerging economies such as India and China are becoming manufacturing hubs for bulk drug intermediates, owing to lower production costs, favorable government policies, and expanding capacities of contract manufacturing organizations (CMOs). This trend is further bolstered by the increasing demand for affordable generics in developing regions.
Meanwhile, the custom intermediates segment is experiencing rapid expansion of which is attributed to the surging demand for highly specific and customized intermediates required in the production of complex drug molecules, including targeted therapies and personalized medicines. Pharmaceutical companies are increasingly relying on contract research and manufacturing services (CRAMS) providers to develop these specialized intermediates, as it offers flexibility, cost-efficiency, and faster time-to-market for new drug formulations.
Product Share () Chemical Intermediates 58.5%The generic drug intermediates segment is anticipated to register a CAGR of 6.4% during the forecast period from to . This remarkable growth trajectory is primarily attributed to the surging demand for cost-effective generic drugs across the globe. Patent expirations of blockbuster pharmaceutical products are creating significant opportunities for generic manufacturers to introduce affordable alternatives, thereby necessitating a higher demand for pharmaceutical intermediates specific to generics.
Furthermore, healthcare cost-containment initiatives by various governments, coupled with the rising geriatric population and increasing prevalence of chronic diseases such as cardiovascular disorders, diabetes, and cancer, are driving the widespread adoption of generics.
Emerging markets, including India, China, Brazil, and South Africa, are rapidly expanding their generic drug manufacturing capacities owing to favorable government policies, low manufacturing costs, and availability of skilled labor. This, in turn, is boosting the requirement for high-quality, competitively priced intermediates tailored for generic drug production.
On the other hand, the branded drug intermediates segment continues to hold a notable share in the pharmaceutical intermediates market, supported by sustained investments in innovative drug discovery and development. Major global pharmaceutical companies are focusing on breakthrough therapies, especially in oncology, rare diseases, autoimmune disorders, and central nervous system (CNS) conditions. These developments demand specialized intermediates that comply with stringent regulatory standards concerning purity, safety, and efficacy.
Although the branded segment exhibits moderate growth compared to the generics sector, the increasing emphasis on biopharmaceuticals, targeted therapies, and high-value specialty medicines ensures steady demand for premium-grade intermediates.
Category CAGR ( to ) Generic Drug Intermediates 6.4%In the pharmaceutical intermediates market, anti-cancer drugs represent the fastest-growing application segment, projected to register a robust CAGR of 7.8% from to . The rise in oncology research, increasing global cancer incidence, and high demand for targeted therapies are key drivers supporting this growth.
Additionally, favorable regulatory support for breakthrough cancer therapies and rising oncology pipeline drugs globally are expected to sustain demand for pharmaceutical intermediates specifically tailored for anti-cancer formulations. Emerging markets such as China, India, and Brazil are also contributing to this growth by expanding their oncology drug manufacturing capabilities, supported by government initiatives to promote local production and reduce dependency on imports.
Analgesics continue to hold a significant market share owing to their consistent demand for pain management across a wide patient base, especially in cases of chronic diseases and post-surgical recovery. The anti-inflammatory drugs segment remains steady, benefiting from the prevalence of autoimmune disorders such as arthritis. Cardiovascular drugs sustain stable market performance driven by the aging population and rising cardiac health concerns globally. Meanwhile, anti-diabetic drugs see steady uptake in response to the growing diabetic population worldwide.
The antimicrobial drugs segment faces both opportunities and challenges due to the emergence of resistant strains, but maintains relevance in global healthcare. The other category covers niche therapeutic areas and contributes modestly to overall demand, catering to specialty and orphan drugs.
Application CAGR ( to ) Generic Drug Intermediates 7.8%Among the various end-user segments in the pharmaceutical intermediates market, the contract manufacturing organizations (CMOs) and contract research organizations (CROs) segment is projected to be the fastest-growing, registering a CAGR of 5.6% between and . This robust growth is largely driven by the increasing trend of outsourcing drug development and manufacturing activities.
Pharmaceutical and biotech companies are increasingly relying on CMOs and CROs to streamline operations, reduce time-to-market, and minimize infrastructure and labor costs. With rising demand for complex and high-quality intermediates, CMOs/CROs are expanding their capabilities to meet global regulatory standards, further fueling their demand and growth in the market.
Biotech and pharmaceutical companies remain the largest end users of pharmaceutical intermediates due to their direct involvement in drug discovery, development, and commercialization. These companies utilize a broad range of intermediaries to develop both generic and branded medications across therapeutic areas.
Their consumption of intermediates is influenced by R&D investments, drug pipeline expansions, and market demand for new and effective treatments. While their growth is steady, it is somewhat moderated compared to CMOs/CROs, as many companies continue to shift production responsibilities externally to reduce costs and improve scalability.
Research laboratories, although a smaller segment in terms of market share, continue to play a vital role in early-stage drug development. These institutions use pharmaceutical intermediates primarily for exploratory research, synthesis of novel compounds, and preclinical studies. Their demand is relatively stable, supported by academic and private-sector funding, as well as government grants for biomedical innovation.
End User CAGR ( to ) CMOs/CROs 5.6%Growth of Pharmaceutical Intermediates Driven by Expanding Generic Drug Market
Globally most healthcare systems are opting ofr options to reduce the cost of drugs that’s leading to the rising uptake of generics. Since generics are chemically similar to that of branded drugs but sold at a lower price the volume of these generics sold is increasing. These intermediates are key for the manufacture of active pharmaceutical ingredients, APIs-the lifeline of generics.
With the expiry of more and more patents for branded drugs, the entry of generics is increasing in the market, these factor contribute to increase in demand for intermediates. Most of the generic drug manufacturers face pressure to maintain cost-effectiveness while meeting quality standards, thus driving the need for efficient and scalable production of intermediates.
The increasing generics market encourages innovation in the manufacture of pharmaceutical intermediates while optimizing synthesis processes, cost economy, and complying with regulatory requirements. That sets a vibrant platform for research and development regarding new intermediates, as well as more effective and efficient manufacturing technology, adding to the growth in the overall market for pharmaceutical intermediates.
Thus, generic drug development not only provides demand to the intermediate's market but encourages its development by way of innovations.
Emphasis on Outsourcing of Production by Specialized Firms Anticipates the Market Growth
With a view to cost reduction, efficiency enhancement, and scaling up of production, several pharmaceutical firms are looking for CMOs that can extend their expertise in handling large volumes of production.
It give them access to better manufacturing capabilities that they could not afford, thus saving on investments in facilities or labor costs. It will also provide more agility in response to market demand fluctuations. Because CMOs produce APIs as well as intermediates, they grow with increasing demand for the pharmaceutical intermediate. This is most visible within the generics market, where there is a very specific need for economical production.
Besides that, with the globalization of the pharmaceutical industry and the emergence of emerging markets, the requirement for effective supply chains has increased. Such outsourcing will mean production by firms with global reach and thus better access to these markets, thereby further increasing demand for intermediates.
In the process, outsourcing manufacturing to specialized firms smoothes production processes, reduces costs, and increases overall demand for pharmaceutical intermediates, which hastens the growth of the market.
Emphasis on Development of Intermediates for Specialized Drugs bring business opportunities for Pharmaceutical Intermediate Manufacturers
There is an up trend towards take up of biologics, biosimilar and personalized medicine. These kind of specialized products require custom and complex intermediates for production. With the rise in incidences of chronic diseases raises the demand for specialized treatments and, subsequently, pharmaceuticals with intermediates to support sophisticated drugs manufacturing.
This trend is a window to pharmaceuticals of high-valued intermediates that are more advanced in technology with specialized expertise. These are generally more difficult to synthesize, creating a market for companies that have the appropriate capabilities in advanced chemistry, biotechnology, and regulatory compliance.
Also, the increasing use of biologics and personalized medicines opens up another befitting opportunity for intermediates manufacturers to extend their product portfolios. With biologics doing a remarkably job of gaining share in the pharmaceutical market, they bring business growth opportunities to the intermediate manufacturers.
As the market for specialty drugs continues to grow, companies that invest in innovation, research, and the development of custom and specialized intermediates are expected to capture a significant share in the market.
Advancements in Complex Intermediates Propel the Expansion of the Pharmaceutical Intermediates Market
The drug development became more sophisticated, with development of biologics, personalized medicines, and advanced therapies, the requirements for complex intermediates also started to increase. It finds its essentiality in manufacturing very special active pharmaceutical ingredients, the basic materials which form targeted therapies, monoclonal antibodies, gene therapies, and peptides.
While biopharmaceuticals and biologics continue to dominate the landscape, the growing demand for highly specialized intermediates is driving innovation and growth within the same intermediates market. These kinds of intermediates are usually more difficult to manufacture because they have very intricate chemical structures, which demand advanced technologies and precision manufacturing capabilities.
Further, a set of technologies in the synthesis-chemistry techniques, such as continuous flow chemistry and biocatalysis, has helped to give back to make the production of complex intermediates more effective, scalable, and cost-effective. Inventions enabling manufacturing companies to increase quality by ensuring consistency improve the overall development cycle of drugs.
Increasing demand for complex intermediates in modern drug manufacturing acts as a driving force in the pharmaceutical intermediate market, creating great business opportunities for those manufacturers who will be able to meet such demands.
Tier 1 companies comprise market leaders with a market revenue of above USD 100 million capturing significant market share of 45.1% in global market. These market leaders are characterized by high production capacity and a wide product portfolio.
These market leaders are distinguished by their extensive expertise in providing their services underpinned by a robust consumer base. Prominent companies within tier 1 include Cambrex Corporation, BASF SE, Aceto Corporation, Interchem, Cambrex Corporation, Arkema Inc.
Tier 2 companies include mid-size players with revenue of USD 50 to 100 million having presence in specific regions and highly influencing the local market and holds around 20.7% market share. These are characterized by a strong presence overseas and strong market knowledge.
These market players have good technology and ensure regulatory compliance but may not have access to global reach. Prominent companies in tier 2 include Chiracon GmbH, Midas Pharma GmbH, Chemcon Specialty, Chemical Pvt. Ltd., Dextra Laboratories Limited, Pfizer, BMSetc.
Finally, Tier 3 companies, act as a suppliers to the established market players. They are essential for the market as they specialize in specific services and cater to niche markets, adding diversity to the industry.
Overall, while Tier 1 companies are the primary drivers of the market, Tier 2 and 3 companies also make significant contributions, ensuring the pharmaceutical intermediates market remains dynamic and competitive.
The section below covers the industry analysis for the pharmaceutical intermediates market for different countries. Market demand analysis on key countries in several regions of the globe, including North America, Asia Pacific, Europe, and others, is provided. While in North America, United States market leads the market with 90.9% in , in Asia Pacific, South Korea is expected witness strong growth of 2.5% by .
Countries Value CAGR ( to ) UK 3.0% China 6.4% India 7.2% Germany 3.3% USA 3.2% Saudi Arabia 2.3%An increased need in biopharmaceutical treatments in a vast manner like monoclonal antibodies, gene therapies, and biologics will propel an increasing rate of patients toward those drugs seeking cure for illnesses like cancer or auto-immunity disorders.
Thus, an urgent requirement of a much more complicated set of these intermediates. The creation of active pharmaceutical ingredients (APIs) through advanced therapies requires high-quality chemical precursors, which involves well-tailored intermediates. Progressions in biotechnology, such as biocatalysis and continuous flow synthesis, are making the manufacture of these molecules more efficient and economical.
As the USA remains at the helm of the global biopharmaceutical innovation landscape, manufacturers of pharmaceutical intermediates are gaining through this increasing market, especially with the acceleration in the shift towards biologics.
The Japanese biopharmaceutical market is moving upwards, and the focus remains on the development of monoclonal antibodies, gene therapies, and cell therapies. With research in these fields advancing, the demand for specialty pharmaceutical intermediates is only expected to continue to grow.
The country has focused on innovation in cancer and autoimmune diseases and neurodegenerative conditions that are driving this need for more intermediates in support of those new therapies. Biocatalysis and continuous flow synthesis have been developed into technologies that reduce the production process for these intermediates, but they are at the same time making it sustainable and cost-effective.
Japan's advanced research in biopharmaceuticals is likely to generate demand for quality intermediates and will open wide avenues for domestic manufacturers.
To date, Germany market boasts of its innovation and technology, yet the pharma industry is not an exemption. The country has been investing significantly in research, especially in cancer, immunology, and rare diseases. New drug development is highly complex chemical processes that require very specialized intermediates to create active pharmaceutical ingredients.
Germany's emphasis on biopharmaceuticals, biologics, and personalized medicine is opening up new treatments and thus a growing demand for specific therapy-related intermediates. Other is the commitment toward the advancement of drug delivery systems and breakthrough therapies, such as gene therapies and monoclonal antibodies, and this requires an even more complex intermediate.
Hence, with ongoing support from public and private sources, Germany shall remain a front-runner in this pharmaceutical intermediates market, accelerating its growth with further innovation.
Substantial investments and focus is seen in the pharmaceutical intermediates industry towards launch of new series of services to the market. Another key strategic focus of these companies is to actively look for strategic partners to bolster their product portfolios and expand their global market presence.
Recent Industry Developments in Pharmaceutical Intermediates Market