Guidance for Industry

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

Draft - Not for Implementation


A. Equipment Design, Size, and Location

Equipment used in the manufacture, processing, packing, or holding of APIs and intermediates should be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

Closed equipment should be used when feasible (i.e., when equipment is located outdoors or in uncontrolled manufacturing environments) to provide adequate protection of APIs and intermediates. When equipment is opened or open equipment is used, appropriate precautions should be taken to prevent contamination or cross-contamination of APIs and intermediates.

B. Equipment Construction and Installation

Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs are not reactive, additive, or absorptive so as to alter the quality and purity of the API and/or intermediate beyond the official or other established specifications. Any substances required for operation, such as lubricants, heating fluids, or coolants, should not contact raw materials, packaging materials, intermediates, or APIs so as to alter the quality and purity of APIs and intermediates beyond the official or other established specifications.

Where feasible, equipment should be designed, constructed, and installed to allow for ease of cleaning, and, as applicable, sanitization. Qualification of equipment should ensure that:

1. It is installed according to approved design specifications, regulatory codes, and the equipment manufacturers’ recommendations; and

2. The equipment operates within limits and tolerances established for the process.

C. Equipment Cleaning and Maintenance Procedures

Written procedures should be established and followed for cleaning and maintaining equipment, including utensils and storage vessels, used in the manufacture, processing, packing, or holding of APIs and intermediates. Procedures should, at a minimum, include:

1. Assigning responsibility for cleaning and maintaining equipment;

2. Establishing maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;

3. Developing a complete description of the methods and materials used to clean and maintain equipment and, when necessary, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning and maintenance;

4. Removing or obliterating previous batch identification;

5. Protecting clean equipment from contamination prior to use;

6. Inspecting equipment for cleanliness immediately before use, if practical; and

7. Establishing the maximum time that may elapse between the completion of processing and equipment cleaning.

D. Equipment Cleaning Methods

Equipment and utensils should be cleaned, held and, where necessary, sanitized at appropriate intervals to prevent contamination or cross-contamination that would alter the quality or purity of the API or intermediate beyond the official or other established specifications.

Dedicated equipment should be cleaned at appropriate intervals to prevent the build-up of objectionable material or microbial growth. As processing approaches the purified API, it is important to ensure that incidental carryover of contaminants or degradants between batches does not adversely impact the established impurity profile. However, this does not generally apply to biologic APIs, where many of the processing steps are accomplished aseptically and where it is often necessary to clean and sterilize equipment between batches.

Nondedicated equipment should be thoroughly cleaned between different products and, if necessary, after each use to prevent contamination and cross-contamination. If cleaning a specific type of equipment is difficult, the equipment may need to be dedicated to a particular API or intermediate.

The choice of cleaning methods, cleaning agents, and levels of cleaning should be established and justified. When selecting cleaning agents (e.g., solvents) the following should be considered:

1. The cleaning agent’s ability to remove residues of raw materials, precursors, by-products, intermediates, or APIs;

2. Whether the cleaning agent leaves a residue itself; and

3. Compatibility with equipment construction materials.

E. Validation of Equipment Cleaning Methods

Equipment cleaning methods should be validated, where appropriate. In general, cleaning validation efforts should be directed to situations or process steps where contamination or incidental carryover of degradants pose the greatest risk to API quality and safety. In early synthesis steps, it may be unnecessary to validate cleaning methods where residues are removed by subsequent purification steps.

Validation of cleaning methods should reflect actual equipment use patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a worst-case API or intermediate can be selected for purposes of cleaning validation. The worst-case selection should be based on a combination of potency, toxicity, solubility, stability, and difficulty of cleaning.

The cleaning validation protocol should describe the equipment to be cleaned, methods, materials, and extent of cleaning, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples (rinse, swabs) to be obtained, and how they are collected, labeled, and transported to the analyzing laboratory.

Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).

Validated analytical methods sensitive enough to detect residuals or contaminants should be in place. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established.

Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits may be established based on the minimum known pharmacological or physiological activity of the API or its most deleterious component.

Equipment cleaning and sanitization studies should address microbiological and endotoxin contamination for those processes intended or purported to reduce bioburden or endotoxins in the API, or other processes where such contamination may be of concern (e.g., nonsterile APIs used to manufacture parenteral products). Cleaning procedures should be checked by appropriate methods after validation to ensure these procedures remain effective when used during routine production. Where feasible, equipment should be examined visually for cleanliness. This may allow detection of gross contamination concentrated in small areas that could go undetected by analytical verification methods.

F. Clean in Place Methods

Where feasible, clean in place (CIP) methods should be used to clean process equipment and storage vessels. CIP methods might include fill and soak/agitate systems, solvent refluxing, high-impact spray cleaning, spray cleaning by sheeting action, or turbulent flow systems.

CIP systems should be subjected to cleaning validation studies to ensure that they provide consistent and reproducible results. When practical, equipment in CIP systems should be disassembled during cleaning validation to facilitate inspection and sampling of inner product surfaces for residues or contamination, even though the equipment is not normally disassembled during routine use.

Once CIP systems are validated, appropriate documentation should be maintained to show that critical parameters (e.g., time, temperature, turbulence, cleaning agent concentration, rinse cycles) are achieved with each cleaning cycle.

G. Automatic, Mechanical, Electronic, and Computer Equipment

Automatic, mechanical, or electronic processing equipment, or other types of equipment, including computers, used in the manufacture of APIs and intermediates should be routinely calibrated, inspected, and checked to ensure proper performance. Written records of those calibration checks and inspections should be maintained.

Written procedures should be established for:

1. System operations;

2. System qualification and validation;

3. Corrective actions to be taken in cases of malfunctions;

4. Detecting and recording errors and implementing corrections;

5. Restarting the system and recovering data;

6. Authorizing, implementing, and recording changes; and

7. Use of electronic signatures.

Systems should be appropriately qualified and validated to demonstrate the suitability of the hardware and software to perform assigned tasks in a consistent and reproducible manner. The depth and scope of validation should depend on the diversity, complexity, and criticality of the system.

All changes to a system should be approved by the quality control unit in advance and performed by authorized and competent personnel. Records should be kept of all changes including modifications and enhancements to the hardware, software, and any other critical components of the system to demonstrate that the modified system is maintained in a validated state.

Procedures should be established to prevent unauthorized entries or changes to existing data. Systems should identify and document the persons entering or verifying critical data. Input to and output from the computer or related system should be checked for accuracy at appropriate intervals. Where critical data are entered manually, there should be an additional check on the accuracy of the entry. This may be performed by a second operator or by the system itself. Appropriate controls should be exercised over computers and related systems to ensure that changes in master production and control records or other records are made only by authorized personnel.

A back-up system should be available to respond to system breakdowns or failures that result in permanent loss of critical records. Back-ups may consist of hard copies or other forms (e.g., tapes or microfilm) that ensure back-up data are exact, complete, and secure from alteration, inadvertent erasure, or loss.


A. General Controls

Written procedures should be established describing the purchase, receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of raw materials. Such procedures should be followed.

Raw materials should be handled and stored in a manner to prevent contamination and cross-contamination. Bagged and boxed raw materials should be stored off the floor and suitably spaced to permit cleaning and inspection. Raw materials that are stored outdoors should be in suitable containers. Identifying labels should remain legible and containers should be appropriately cleaned before opening to prevent contamination.

For solvents or reagents delivered in bulk vessels (e.g., tanker trucks), a procedural or physical system, such as valve locking or unique couplings, should be used to prevent accidental discharge of the solvent into the wrong storage tank.

Each container or grouping of containers of raw materials should be assigned and identified with a distinctive code, lot, or receipt number. This code should be used in recording the disposition of each lot. A system should be in place to identify each lot’s status. Large containers (e.g., tanks,

silos) that are used for storing raw materials, including their attendant manifolds, filling and discharge lines, should be appropriately identified.

B. Receipt, Sampling, Testing, and Approval of Raw Materials

Upon receipt and before acceptance, each container or grouping of containers of raw materials should be examined visually for appropriate labeling, container damage, seal integrity (where appropriate), and contamination. Raw materials should be held under quarantine until they have been sampled, tested or examined, as appropriate, and released for use.

Representative samples of each shipment of each lot should be collected for testing or examination in accordance with an established procedure. The number of containers to sample and the sample size should be based upon appropriate criteria (e.g., raw material variability, confidence levels, degree of precision desired, past quality history of the supplier, and the quantity needed for analysis). Raw material containers selected for sampling should be opened, sampled, and resealed in a manner that prevents contamination of their contents and of other raw materials. Sample containers should be properly identified.

At least one test should be conducted to verify the identity of each raw material. A supplier's certificate of analysis might be used in lieu of performing other testing provided that the manufacturer has a system in place to evaluate vendors and establishes the reliability of the supplier’s test results at appropriate intervals. For hazardous or highly toxic raw materials, where on-site testing may be impractical, suppliers’ certificates of analysis should be obtained showing that the raw materials conform to specifications. In addition, the identity of these raw materials should be confirmed by examination of containers and labels. The lack of on-site testing for hazardous raw materials should be documented.

C. Use and Reevaluation of Approved Raw Materials

Approved raw materials should be stored under suitable conditions, and where appropriate, rotated so that the oldest stock is used first. Raw materials should be reevaluated, as necessary, to determine their suitability for use (e.g., after prolonged storage or after exposure to heat or high humidity).

D. Rejected Raw Materials

Rejected raw materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

E. Control of Recovered Solvents, Mother Liquors, and Second Crops

Written procedures should be established for the recovery of solvents, mother liquors, second crops or other materials. These should include adequate tests and controls to ensure that recovered materials are suitable for use in manufacturing processes and do not adversely affect the quality of APIs and intermediates.

Solvents may be recovered and reused in the same process or in different processes, provided that the recovery procedures are validated to ensure that recovered solvents meet appropriate standards before reuse or commingling with other approved materials. The quality of solvent mixtures should be monitored at suitable intervals.

Mother liquors may be reused provided that the quality of the API or intermediate is not adversely affected by their reuse. Procedures for secondary recovery of reactants, intermediates, or the API should ensure that these recovered materials meet specifications suitable for their intended use.

The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented in batch production records.

F. Process Water Quality

Water used in the production of APIs should be routinely tested and, at a minimum, meet the standards for potable water, as stated in the United States Environmental Protection Agency's (EPA) National Primary Drinking Water Regulations (NPRDWR) or comparable standards of other authorities such as the European Union, Japan, or the World Health Organization. The potable water supply, regardless of source, should be assessed for chemicals that may affect the API process. Information should be periodically sought from local authorities concerning potential contamination by pesticides or other hazardous chemicals.

Water of suitable quality, with tighter chemical and microbiological quality specifications, should be used during certain process steps (e.g., cell cultures, final crystallization and isolation) and during early process steps if impurities that affect API quality are present in the water and cannot be removed in later steps. For example, if water is used for a final wash of a filter cake, or if the API is crystallized from an aqueous system, the water should be suitably treated (e.g., deionization, ultrafiltration, reverse osmosis, or distillation) and routinely tested to ensure compliance with appropriate chemical and microbiological specifications. If used for final rinses during equipment cleaning, the water should be of the same quality as that used in the manufacturing process.

Water used in the final isolation and purification steps of nonsterile APIs intended for use in the preparation of parenteral products should be tested and controlled for bioburden and endotoxins.

Where water is treated to achieve an established quality, the treatment process and associated distribution systems should be qualified, validated, maintained, and tested following established procedures to ensure water of the desired quality.

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