Pharmaceutical ingredients for both human and veterinary preparations.

Sometimes several firms cooperate in the production (including packaging and labelling) of an active pharmaceutical ingredient. It may also happen that a finished, packed, and labelled active pharmaceutical ingredient is repacked and/or relabelled and given a new designation. Since such procedures constitute part of a manufacturing operation, they should be subject to the relevant guidelines set out below.
The practices outlined below are intended to apply to active pharmaceutical ingredients for both human and veterinary preparations.
Personnel
Each firm should employ personnel with the necessary qualifications and competence for the production and quality control of active pharmaceutical ingredients. There should be an adequate number of staff with appropriate education, technical knowledge, and practical experience related to the job they perform.
The firm should have a defined organization represented in a chart. Individual responsibilities should be laid down in written instructions, to ensure that there are no gaps or overlaps. The responsibilities placed on any one individual should not be so extensive as to incur any risk to quality.
Staff at all levels should be adequately trained for the tasks and responsibilities assigned to them.
Measures should be taken to ensure that no person affected by a disease in a communicable form or having open lesions on the exposed surface of the body is engaged in any production step involving direct contact with the active pharmaceutical ingredients.
Premises
Premises, including areas containing open tanks, should be of suitable construction. They should provide a suitable environment for manufacturing operations and should be adequately adapted to and of a sufficient size for their intended use. The premises should not contribute to actual or potential mix-ups or contamination of the active pharmaceutical ingredients. The arrangement should provide for a logical work flow.
For special purposes, such as the production of sterile products and of certain antibiotics, hormones, and cytostatic substances, separate specifically designed enclosed areas with completely separate air-handling systems should be provided.
To maintain hygienic working conditions, the premises should include facilities for changing clothes, washing, and toilet purposes as well as for eating, drinking, and smoking.
Equipment
Manufacturing equipment should be designed, constructed, located, and maintained in such a way as to:
(a) be suitable for its intended use;
(b) facilitate thorough cleaning;
(c) minimize the risk of contamination of products and containers during production; and
(d) facilitate efficient and, if applicable, validated and reliable operation.

application of cGMP

Since there are fundamental distinctions between the production of bulk active pharmaceutical ingredients and the formulation of finished pharmaceutical products, the strict application of GMP as set forth in the main part of this guide is not always practical or necessary. The present supplementary guidelines outline procedures and practices that manufacturers should employ to ensure that the methods, facilities, and controls used for the production of active pharmaceutical ingredients are operated or managed so that such products have the quality and purity appropriate for their use in finished pharmaceutical products.
General considerations
In the manufacture of active pharmaceutical ingredients, overall control is essential to ensure high quality. Haphazard operations cannot be permitted in the manufacture of substances that may be used to save life or to restore or promote health.
Recommended practices for the manufacture of active pharmaceutical ingredients are set out below. Adherence to these practices, complementing the various control tests carried out from the beginning to the end of the production cycle, will contribute substantially to the production of consistently uniform batches of high-quality active pharmaceutical ingredients.
The manufacturer must assume responsibility for the quality of the active pharmaceutical ingredients produced. The manufacturer alone can avoid mis-takes and prevent mishaps by exercising adequate care in both production and control procedures. Full evidence of compliance with GMP should be given from the step from which the processes or the starting materials used have a critical influence on the quality of the active pharmaceutical ingredient. This step should be determined in each individual case by agreement between the competent authority and the manufacturer.
The good practices outlined below should be considered general guides; whenever necessary, they may be adapted to meet individual needs provided the established standards of quality of the active pharmaceutical ingredients are still achieved. The good practices are intended to apply to the manufacturing processes (including packaging and labelling) used in the production of active pharmaceutical ingredients.

REGULATORY APPROACH

One goal of this guidance is to tailor the Agency's usual regulatory scrutiny to meet the needs of PAT-based innovations that (1) improve the scientific basis for establishing regulatory specifications, (2) promote continuous improvement, and (3) improve manufacturing while maintaining or improving the current level of product quality assurance. To be able to do this, manufacturers should communicate important scientific knowledge to the Agency and resolve related technical issues in a timely manner. Our goal is to facilitate a flexible regulatory assessment involving multiple Agency offices with varied responsibilities.

This guidance provides a broad perspective on our proposed PAT regulatory approach. Close communication between the manufacturer and the Agency’s PAT review and inspection staff will be a key component in this approach. We anticipate that communication between manufacturers and the Agency will continue over the life cycle of a product and that communication will be in the form of meetings, telephone conferences, and written correspondence. Any written correspondence should be identified clearly as Process Analytical Technology or PAT. All marketing applications, amendments, or supplements to an application should be submitted to the appropriate CDER or CVM division in the usual manner.

We recommend general correspondence related to PAT be directed to our new FDA PAT Team. Manufacturers can also contact the PAT Team regarding any PAT questions or issues related to nonapplication drug products or not pertaining to a specific submission or application at the address below.

FDA Process Analytical Technology Team
Office of Pharmaceutical Science, HFD-003
Center for Drug Evaluation and Research
5600 Fishers Lane
Rockville, MD 20857

For currently approved products, during their planning phase, manufacturers should consider the effects of PAT on the current process, in-process controls, and specifications. When consulting with the Agency, manufacturers may want to discuss not only specific PAT plans, but also thoughts on a possible regulatory path.

This guidance is also intended to encourage research to explore suitability and validation strategies for new technologies prior to planning and implementing PAT-based manufacturing. If research is conducted in a production facility, it should be under the facility's own quality system. Information generated from this research along with other information that provides process understanding can be used to formulate and communicate implementation plans to Agency staff. Plans for implementing and regulatory assessment of PAT can be agreed to with the Agency through a variety of communication channels.

Section 116 of the 1997 Food and Drug Administration Modernization Act amended the Food, Drug, and Cosmetic Act by adding section 506A (21 U.S.C. 356a), which provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes. We recommend that manufacturers continue to consider all relevant FDA guidance documents for recommendations on the information that should be submitted to support a given change.

In general, PAT implementation plans should be risk based. We are proposing the following possible implementation options:

• PAT can be implemented under the facility's quality system; CGMP inspections by the Agency follow.
• PAT can be implemented following CGMP inspection by the PAT Team.
The PAT Team can assist manufacturers with pre-operational review of the PAT manufacturing facility and process (ORA Field Management Directive NO. 135). The recommendations in the inspection report will serve as a summary basis of final approval of the process and be filed in the relevant application, where needed, and facility databases within the Agency.
• A supplement (CBE, CBE-30 or PAS) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT Team or PAT certified investigator before implementation.
• A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies and time lines. Following approval of this comparability protocol by the Agency, one or a combination of the above regulatory pathways can be adopted for implementation.
It should be noted that when certain PAT implementation plans neither affect the current process nor require a change in specifications, several options can be considered. manufactures should evaluate and discuss with the Agency the most appropriate option for their situation.

Regulatory Strategies

The Agency understands that to enable successful implementation of PAT, flexibility, coordination, and communication with manufacturers is critical. The Agency believes that current regulations are sufficiently broad to accommodate these new strategies. Regulations can effectively support innovation (e.g., new drugs and drug delivery systems) as long as clear communication mechanisms exist between the Agency and industry, for example, in the form of meetings or informal communications between the Agency and manufacturers during drug development.

The first component of the PAT framework described above addresses many of the uncertainties with respect to new technologies and outlines broad principles for addressing anticipated scientific and technical issues. This information should assist a manufacturer who is proposing to the Agency innovative technologies that may call for a new regulatory path. The Agency encourages such proposals and has developed new regulatory strategies to consider such proposals. The Agency's new regulatory strategy includes (1) a PAT team approach for CMC review and CGMP inspections; (2) joint training and certification of PAT review, inspection and compliance staff; (3) scientific and technical support for the PAT review, inspection and compliance staff; and (4) the recommendations provided in this guidance.

The recommendations provided in this guidance are intended to alleviate the fear of delay in approval as a result of introducing new manufacturing technologies. Ideally PAT principles and tools should be introduced during the development phase. The advantage of using these principles and tools during development is to create opportunities to improve the mechanistic basis for establishing regulatory specifications. Manufacturers are encouraged to use the PAT framework to develop and discuss approaches for establishing mechanistic-based regulatory specifications for their products.

We also encourage the use of PAT strategies for the manufacture of currently approved products. Manufacturers may want to evaluate the suitability of a PAT tool on experimental and/or production equipment and processes. For example, when evaluating experimental on- or in-line process analyzers during production, it is recommended that risk analysis of the impact on product quality be conducted before installation. This can be accomplished within the facility's quality system without prior notification to the Agency. Data collected using an experimental tool should be considered research data.

When using new measurement tools, such as on/in-line process analyzers, certain data trends that may be intrinsic to the current acceptable process may be observed. Manufactures should scientifically evaluate these data to determine how or if such trends affect quality and implementation of PAT tools. FDA does not intend to inspect research data collected on an existing product for the purpose of evaluating the suitability of an experimental process analyzer or other PAT tools. FDA's routine inspection of a firm's manufacturing process that incorporates a PAT tool for research purposes will be based on current regulatory standards (e.g., test results from currently approved or acceptable regulatory methods). Any FDA decision to inspect research data would be based on exceptional situations similar to those outlined in Compliance Policy Guide Sec. 130.300. Those data used to support validation or regulatory submissions will be subject to inspection in the usual manner.

Integrated Systems Approach

The fast pace of innovation in today's information age necessitates integrated systems thinking for evaluating and timely application of efficient tools and systems that satisfy the needs of patients and the industry. Many of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information/knowledge management functions so closely together that these four areas should be coordinated in an integrated manner. Therefore, upper management support for these initiatives is critical for successful implementation.

Drug formulations and manufacturing processes

Design and optimization of drug formulations and manufacturing processes within the PAT framework can include the following steps (the sequence of steps can vary):

• Identify and measure critical material and process attributes relating to product quality
• Design a process measurement system to allow real time or near-real time (e.g., on-, in-, or at-line) monitoring of all critical attributes
• Design process controls that provide adjustments to ensure control of all critical attributes
• Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes
Therefore, it is important to emphasize that a strong link between product design and process development is essential to ensure effective control of all critical quality attributes. Process monitoring and control strategies are intended to monitor the state of a process and actively manipulate it to maintain a desired state. Strategies should accommodate the attributes of input materials, the ability and reliability of process analyzers to measure critical attributes, and the achievement of pre-established process endpoints to ensure consistent quality of the output materials and the final product.

Within the PAT framework, a process endpoint need not be a fixed time, but can be the achievement of the desired material attribute. This, however, does not mean that process time is not considered. A range of acceptable process times (process window) is likely to be achieved during the manufacturing phase and should be evaluated, and considerations for addressing significant deviations from acceptable process times should be developed. Process end points intended for use in real time release should be considered more critical than those that are only used for in-process control.

Where PAT spans the entire manufacturing process, the fraction of in-process materials and final product evaluated during production could be substantially greater than what is currently achieved using laboratory testing. Thus, an opportunity to use more rigorous statistical principles for a quality decision is provided. Multivariate Statistical Process Control can be feasible and valuable to realizing the full benefit of real time measurements. Similarly, rigorous statistical principles should be used for defining acceptance criteria for end product attributes (e.g., content uniformity) that take into consideration differences in the nature of the test (e.g., continuous monitoring) and sample size between an on-line test and a current laboratory test.

Real time or near real time measurement tools typically generate large volumes of data. Certain data are likely to be relevant for routine quality assurance and regulatory decisions. In a PAT environment, batch records should include scientific and procedural information indicative of high product and process quality. For example, batch records could include a series of charts depicting acceptance ranges, confidence intervals, and distribution plots (inter- and intrabatch) showing measurement results. Ease of secure access to these data is important for real time manufacturing control and quality assurance. Installed information technology systems should accommodate such functions.

Technologies that incorporate greater product and process understanding can provide a high assurance of quality on every batch and provide alternative, effective mechanisms to achieve validation. In a PAT framework, process validation can be enhanced and possibly consist of continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process endpoints.
Installation of process analyzers on existing process equipment in production should be done after risk-analysis to ensure this installation does not adversely affect the process or product quality (i.e. qualified equipment and validated process). Based on this assessment, it should be decided if the existing process should be revalidated or not.

Risk-based approaches are suggested for validation of PAT software systems. The recommendations provided by other FDA guidances such as General Principles of Software Validation should be considered. Other useful information can be obtained from consensus standards, such as ASTM and Good Automated Manufacturing Practices (GAMP) listed in the bibliography section.

Pharmaceutical manufacturing processes

Pharmaceutical manufacturing processes often consist of a series of unit operations, each intended to modulate certain properties of the materials being processed. To ensure acceptable and reproducible modulation, consideration must be given to the quality attributes of incoming materials and their process-ability for each unit operation. During the last 3 decades, significant progress has been made in developing analytical methods for chemical attributes (e.g., identity and purity). However, certain physical and mechanical attributes (e.g., particle shape, size distribution, inter- and intra-particulate bonding) of pharmaceutical ingredients are relatively difficult to characterize, and adverse effects due to inherent quality variability are often not recognized until after manufacture. Establishing effective standards or specifications for physical attributes of raw (e.g., excipients) and in-process materials poses a significant challenge because of the complexities of such attributes (e.g., particle shape and shape variations within a sample) and because of difficulties related to collecting representative powder samples for testing. It is well known that powder sampling procedures can be prone to sampling errors.

Formulation design strategies exist that provide robust processes that are not adversely affected by minor differences in physical attributes of raw materials. Because these strategies are not generalized and are often based on the experience of a particular formulator, the quality of these formulations can only be evaluated by testing samples of in-process materials and end products. Currently, these tests are performed off line after preparing collected samples for analysis. Different tests, each for a particular quality attribute (e.g., content uniformity, moisture content, dissolution rate), are needed because such tests only address one attribute of the active ingredient following sample preparation (e.g., chemical separation to isolate it from other components). During sample preparation, other valuable information pertaining to the formulation matrix is often lost. Several new technologies are now available that can acquire information on multiple attributes with minimal or no sample preparation. These technologies provide an opportunity to assess multiple attributes, often nondestructively.

Currently most pharmaceutical processes are based on time defined end points (e.g., blend for 10 minutes). However, in some cases, these time defined end points do not completely take into consideration physical differences in raw materials (e.g., excipients). Processing difficulties can arise that result in failure of the product to meet specifications, even if certain raw materials conform to established specifications.