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. ). 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:
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).
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/
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
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/
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/
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:
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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Optimum Selection of Pharmaceutical Intermediates can make your Manufacturing Business Profitable and Sustainable
Do you know Why some Pharmaceutical Intermediate Manufacturers are Flourishing in today&#;s Competitive Business Environment while others are Struggling?
Because their Businesses are based on Solid Foundation. And when it comes to Business Foundation, Product Selection is one of the most important Business Aspect.
They are selecting the right Pharmaceutical intermediate Molecules for their Manufacturing Business based on Integrated Product Selection Process
Before getting into the details, let me ask you an important question:
If you are looking for more details, kindly visit hait.
Do you know what&#;s the most important criteria to make any business successful?
It&#;s the Value Addition potential. Because unless the business adds significant value it can&#;t succeed.
Here your manufacturing business is no exception. Unless you add tremendous value in your pharmaceutical intermediate manufacturing business you can&#;t think of making it profitable and sustainable. Isn&#;t it?
Now the question is how to add tremendous value?
Making Medicines at Affordable Prices
When it comes to pharmaceutical intermediate manufacturing business, you can do it by helping the pharmaceutical industries become efficient. Then only they can make the life-saving medicines available to all at affordable prices.
Do you know why the medicines are so powerful and effective against the diseases?
It&#;s because of the active pharmaceutical ingredients. In fact, these active molecules actually fight with the diseases. In order to be effective, the medicines must be formulated with those active pharmaceutical ingredients.
But the active pharmaceutical ingredients must be manufactured at large scale in sufficient quantities at reasonable costs. Why?
Because in order to make medicines available to all of us at affordable prices, active pharmaceutical ingredients must be available at reasonable costs.
But how to do that?
That&#;s possible only when you manufacture high quality active pharmaceutical ingredient molecules at low costs.
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. Of course, some of the molecules are manufactured by other processes.
Irrespective of which manufacturing processes are employed, making active pharmaceutical ingredient molecules is challenging. Because the manufacturing process is complex and time consuming.
With chemical synthesis, process involves multiple reaction steps along with complex reaction mechanisms.
That&#;s why it makes business sense to make the manufacturing of active pharmaceutical ingredient molecules easy. Isn&#;t it?
That&#;s where the pharmaceutical intermediates become important.
Pharmaceutical Intermediates
Because with the pharmaceutical intermediates, the manufacturers of active pharmaceutical ingredient molecules need not start from the basic stage. They can carry out a few final manufacturing steps and the product is ready.
In short, active pharmaceutical ingredient manufacturers can concentrate on their core business.
When you talk about the Pharmaceutical Intermediates, they&#;re nothing but these Intermediate Molecules.
Let&#;s know more the Pharmaceutical Intermediates.
Based on their usage, they can be classified into two categories:
Basic Pharmaceutical Intermediate
When you get into the details of the basic pharmaceutical intermediate molecules, you&#;ll find them to be relatively simple. That&#;s why most of them are less expensive. They&#;re generally used in the initial steps of the manufacturing processes used for making active pharmaceutical ingredients.
Advanced Pharmaceutical Intermediate
When you get into the details of the advanced pharmaceutical intermediate molecules, you&#;ll find them to be structurally complex. That&#;s why most of them are expensive. They&#;re generally used in the final steps of the manufacturing processes used for making active pharmaceutical ingredients.
Before getting into the details of selecting right pharmaceutical intermediates, you need to know how they&#;re manufactured.
Manufacturing Process Details
If you study the manufacturing processes of pharmaceutical intermediates molecules, you&#;ll find four different types:
Based on the techno-economic feasibility, different manufacturing processes are used to make the pharmaceutical intermediates molecules. But when you get into the manufacturing processes employed in the industry, you&#;ll find most of them to be based on chemical synthesis.
Based on Chemical Synthesis
In most of the manufacturing processes, you bring about the molecular changes to the raw material molecules to make the products. And it results in molecular conversion. Here the raw material molecules are changed to the product molecules.
But when you&#;re using chemical reactions to bring about the changes in the molecules, you&#;re using the power of chemical synthesis. Of course, there&#;re different types of reactions to make different products. Naturally each reaction has its own process conditions along with the advantages and disadvantages.
You start with using chemical synthesis to make the products. But then the product molecules are still in the reactor along with other undesired molecules. T
hat&#;s why you need to isolate them in pure form. And you need suitable separation processes to recover them followed by purification processes to purify them. Because it&#;s necessary to make them suitable for the customers.
Based on Fermentation Process
With pharmaceutical intermediates especially the advanced intermediates, sometimes the molecules you want to make are too complex. Because of the molecular complexity, the chemical synthesis-based processes fail to achieve required molecular conversion economically. Then you need to think of alternatives like fermentation.
Fermentation process makes use of the power of the microorganisms. Specially developed microorganisms are grown in the fermentors under optimized process conditions in order to make those molecules. Of course, for different products you need different types of microorganisms.
Again, the fermentation process only makes the products. That&#;s why proper separation and purification processes become essential. This is to recover and purify the products from the fermented broth in order to make them suitable for the customers.
Of course, with pharmaceutical intermediates there&#;s additional advantage in using fermentation processes. Because the fermentation is a bioprocess, the products made by fermentation are chiral compounds which are difficult to make with chemical synthesis. Additionally, fermentation is a green process alternative.
Based on Enzymatic Reactions
When you study the metabolic processes in the body of the living organisms, you&#;ll find them to consist of enzymatic reaction. These biochemical processes are catalyzed by enzymes. That&#;s why enzymes are called biocatalysts.
Because of the advantages, enzymes are made by bioprocesses like fermentation and used as catalysts in molecular synthesis. In fact, when you combine the chemical synthesis and enzymatic reactions, the manufacturing process becomes highly efficient. They&#;re call chemo-enzymatic processes.
And the chemo-enzymatic processes are powerful enough to make complex pharmaceutical intermediate molecules economically and sustainably.
By Extracting from Natural Sources
If you search for special molecules, you&#;ll find that natural sources are the best option. Many useful products can be extracted from them.
When you analyze the compositions in the plant kingdom, you&#;ll be amazed at the product stock. Because the plants make many exotic molecules through enzymatic biochemical processes in the plant cells.
Most of the times, all parts of the plant like leaves, seeds, fruits, flowers, and barks are used to extract useful products. But the product recovery process is very complex. Because the plant feedstocks consist of thousands of molecules, you need proper separation and purification processes to achieve the desired product quality.
As we&#;ve discussed earlier, the product selection is important especially when you&#;re talking about the pharmaceutical intermediates. And Integrated Product Selection process can do justice to this important business initiative.
Integrated Product Selection
In today&#;s competitive business environment, the single most criteria for industrial success is to make your manufacturing process cost-efficient, environment friendly, profitable and inherently safer.
Then only you can think of making your manufacturing business profitable and sustainable. Isn&#;t it?
But everything starts with the product selection. Because product Selection is important for both new projects as well as for replacement of the existing products.
And when you consider the manufacturing complexity and specialized market requirements, the product selection becomes challenging. Because based on the type of the molecules, the manufacturing technologies are different.
And the quality requirements are very stringent. The pharmaceutical intermediates are considered to be building blocks of active pharmaceutical ingredients and so the product quality is important.
You must make those molecules which have got high demand in the market and fetch good prices. It&#;s important that these products match your manufacturing expertise and marketing capabilities.
You can use multiple routes of synthesis and different manufacturing technologies to make the molecules. But this makes the product selection difficult. In order to make your business profitable and sustainable you must consider important business parameters to evaluate the products.
Techno-commercial optimization following an integrated approach can help a lot here.
That&#;s why the molecule selection must be based on evaluation against important techno-commercial business parameters.
Let&#;s consider some business parameters:
Evaluate the Technical Feasibility
The technical feasibility is of utmost importance. Why?
As we&#;ve discussed earlier, manufacturing pharmaceutical intermediates at commercial scale is quite challenging. Because you need to make sufficient quantities of products at affordable costs along with meeting the product quality requirements consistently. Of course, you can&#;t compromise on the environment and safety aspects.
With pharmaceutical intermediates the customers are the manufacturers of active pharmaceutical ingredients. So, they&#;ll ask for high quality products.
When you talk about the process technologies, the manufacturing processes are important. Because the process must be suitable for large scale manufacturing.
In fact, technical feasibility is critical for the success of any process or product idea. And that&#;s why you need to focus on critical technical aspects to evaluate whether the manufacturing process technically feasible or not.
Some of the technical aspects you can consider are mentioned below:
Manufacturing Process must be Suitable of Commercial Scale
The manufacturing process must be suitable for large scale operation. Then only you can meet the business objectives. if you get into the details of the manufacturing process, you&#;ll be able to evaluate the process steps against important technical parameters
Some of the process aspects you can focus on are as below:
In short, the manufacturing process must be cost-efficient and operation friendly. The plant design should preferably use standard process industry equipment and systems. Because it&#;s not a good idea to design specialized devices unless the process demand is critical for manufacturing.
Optimize the Material of Construction
In designing the manufacturing facility for making pharmaceutical intermediates, the material of construction is very important.
Different type of process equipment and systems are used to carry out the different unit processes and unit operations at the commercial scale. Naturally the materials from which they&#;re constructed will depend upon the characteristics of the materials handled and the process conditions maintained.
That&#;s what makes the selection of material of construction challenging. Why?
Because the manufacturing processes vary a lot from product to product as they depend on the process technologies.
Of course, every process has its own material characteristics and so the corrosion potential. So, you need to select the material of construction so as to avoid corrosion which is essential for the long life of the plant hardware.
Sometimes the process conditions make the selection of material of construction difficult. Because if the process parameters involve extreme conditions, you need specialized process equipment using special material of constructions. This results in increasing the capital investment.
Process Parameters Maintenance
When you&#;re interested in operating the manufacturing plant at optimum condition, you need to maintain the process parameters properly. Because maintaining the optimum condition is critical for the success of the manufacturing process.
Some process parameters call for your attention:
Product Quality Requirement
When the product quality requirements are very stringent, you need to ensure the technical feasibility very carefully. Because the product quality depends on multiple technical parameters. Sometimes it becomes very difficult to achieve the required product quality.
Some technical aspects you can focus on are as below:
We&#;ve already checked the technical feasibility. Let&#;s now talk about process safety aspects. Because the design and operation of the manufacturing facility must be inherently safer.
Safety Aspects are Critical
Most of the pharmaceutical intermediates especially the advanced intermediates are made by using multi-step conversion processes. Though most of them have high hazard potential, we don&#;t have any other option then to make the molecules at large scale even if there&#;re safety issues.
Safer Manufacturing Process
So, the best way is to make the manufacturing processes safer. We need to follow safety-based design by incorporating safety aspects in designing the manufacturing facility.
You can consider two approaches:
As you can see when you talk about manufacturing pharmaceutical intermediates, eliminating or at least minimizing the process safety hazards helps a lot. In fact, it&#;s very effective in the early stages of product or process development. Why?
Because in the early stages, the scientists and engineers associated with the process development and plant design have enough freedom to select the products and process technologies. In fact, they can always incorporate the technological advances to minimize the safety hazards to a great extent and make the process inherently safer.
That&#;s how you can evaluate the products against the safety aspects. Looking to the criticality safety aspects must be deciding in the product selection process.
Now, let&#;s talk about environmental sustainability.
Ensure Environmental Sustainability
Environmental sustainability is of utmost importance because most of the processes for making pharmaceutical intermediates generate significant quantities of waste. And most of them are pollutants impacting the environment badly. That&#;s why the pollution control becomes essential.
In that situation, how to achieve it economically is of major importance. Because the waste treatment cost plays a very important role in making the manufacturing process economically viable.
So, you need to go for minimization of waste generation and efficient waste treatment.
Minimize the Generation of Wastes
The most effective pollution control initiative is to minimize the waste generation. When you generate less waste, you need to treat less amount of waste. And you gain in two ways. Both the capital investment in building the waste treatment facility and the operating costs decrease significantly.
You can implement improvement initiatives:
When you go for integrated optimization of the conversion as well as separation and purification processes, you can reduce waste generation significantly.
And when you implement the resources conservation initiatives like Reduce, Reuse, Recover, and Recycling effectively, you can achieve significant reduction in the waste generation.
But as you can&#;t make the waste generation zero, you have to go for efficient waste treatment. So that you can make the wastes harmless to the environment.
Cost-Efficient Waste Treatment
Waste treatment in pharmaceutical intermediate manufacturing is very important. It starts with waste stream characterization and segregation of the waste streams based on their characteristics. Because it&#;s necessary to achieve economical waste treatment by using suitable treatment technologies for different waste streams.
Let&#;s now discuss about the most important aspect of any business &#; the business profitability.
Business Profitability is Important
When you go for pharmaceutical intermediate manufacturing business, you employ the resources to make the products. And you pay for buying the resources. As your products add value to the customers, they pay you at the market rate to purchase your products.
When the business is healthy the money you get from your customers is higher than the money you spent in arranging for the resources.
And the difference is Profit&#;
But how to check whether your business is profitable or not?
Market Demand
You must ask yourself critical questions regarding the market situation:
Of course, things are not certain. However, a careful market analysis can help a lot.
Let&#;s now talk about the other equally important contributor to the profitability &#; the manufacturing cost. In fact, the manufacturing cost can make all the difference between the success and failure of your business.
Manufacturing Cost
In order to evaluate this critical business aspect, you must focus on the total manufacturing cost.
Because, the manufacturing cost must include all expenditures. For that you must check all the cost components:
The cost of the Raw Materials
In manufacturing pharmaceutical intermediates, the raw materials cost must consider the costs of key starting materials, reagents, catalyst, solvents and other raw materials.
The cost of Energy
When you talk about the cost of energy, it will include the electricity and the fuel used for utility generation.
The cost of Waste Treatment
The cost of Waste Treatment will include the cost of raw materials and energy consumed in the treatment of the waste streams.
The cost of Finances
The cost of Finances will include the interest and depreciation based on the capital you&#;ve invested in building the manufacturing facility and other business investments.
Of course, there&#;ll be many other costs associated with the business. The idea is to consider all expenses in order to make the costing accurate.
When you select the pharmaceutical intermediate molecules, make sure to estimate the manufacturing costs and market scenario as accurately as possible.
Alternative Products
But considering the uncertainties, evaluate alternative products to achieve hundred percent plant capacity utilization even when your exiting products have lost their market.
With pharmaceutical intermediate, it&#;s important as the products are specific to the active pharmaceutical ingredients.
The aim is to utilize the manufacturing facility efficiently so that you can maximize the business profitability. Then only you can maintain the profitability even in difficult situations.
It&#;s important to go for complete evaluation for the additional pharmaceutical intermediate even if you&#;re not planning to make then in the near future.
Let&#;s Conclude
In order to build a strong business foundation for manufacturing pharmaceutical intermediates, you must select the right molecules to manufacture.
And the selection of profitable and sustainable pharmaceutical intermediates calls for careful consideration of multiple techno-commercial aspects:
Technical Feasibility
In order to check Technical Feasibility, you must focus on:
Process Safety
In order to ensure Process Safety, you must focus on:
Environmental Sustainability
In order to ensure Environmental Sustainability, you must focus on:
Business Profitability
In order to check the Business Profitability, you must focus on:
As all the Business Aspects are Interdependent, the Product Selection process must consider the critical business aspects in an integrated way.
Let&#;s join hands in using innovations in Selecting Pharmaceutical Intermediates and developing them further to make high-quality medicines available to all at affordable prices.
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